OBLAST PRONALASKAOBLAST PRONALASKA
Predmetni pronalazak se odnosi na tabletu farmaceutski prihvatljiviih soli bupropiona sa modifikovanim otpuštanjem, poželjno bupropion hidrohlorida.The present invention relates to a tablet of pharmaceutically acceptable modified release salts of bupropion, preferably bupropion hydrochloride.
POZADINA PRONALASKABACKGROUND OF THE INVENTION
Bupropion je antidepresant koji hemijski nije srodan triciklicima, tetraciklicima, selektivnim inhibitorima preuzimanja serotonina (SSRI) ili drugim poznatim antidepresivnim agensima. Ovaj lek podseća na psiho-stimulans u smislu svojih neurohemijskih i bihejvioralnih profila in vivo, ali pri klinički prepisanim dozama kod ljudi ne proizvodi pouzdano efekte slične psiho-stimulansu. Njegova struktura blisko podseća na strukturu dietilpropiona i srodna je feniletilaminima. Označena je kao (±)-l-(3-hlorofenil)-2-[(l, l- dimetiletil)amino]-l-propanon hidrohlorid i generičkim imenom amfebutamoh hidrohlorid. Bupropion hidrohlorid je na tržištu dostupan kao. proizvod sa trenutnim otpuštanjem (Wellbutrin®) i kao proizvod sa retard režimom otpuštanja (x 100 mg prikazani su na crtežima 6A-E respektivno.Bupropion is an antidepressant chemically unrelated to tricyclics, tetracyclics, selective serotonin reuptake inhibitors (SSRIs), or other known antidepressant agents. This drug resembles a psychostimulant in terms of its neurochemical and behavioral profiles in vivo, but at clinically prescribed doses in humans it does not reliably produce psychostimulant-like effects. Its structure closely resembles that of diethylpropion and is related to phenylethylamines. It is designated as (±)-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-propanone hydrochloride and generically amphebutamoch hydrochloride. Bupropion hydrochloride is commercially available as immediate release product (Wellbutrin®) and as a delayed release product (x 100 mg are shown in Figures 6A-E respectively.
Wellbutrin® SR i Zyban®). I Wellbutrin® SR i Zyban®su hemijski i farmaceutski identični.Wellbutrin® SR and Zyban®). Both Wellbutrin® SR and Zyban® are chemically and pharmaceutical identical.
Neurohemijski mehanizam antidepresivnog efekta bupropiona nije dobro poznat. Bupropion ne inhibira monoamin oksidazu. Bupropion utiče na hemijske supstance u mozgu koje nervi koriste za slanje poruka jedni drugima. Ove hemijske poruke se nazivaju neurotransmiteri. Neurotransmiteri koje nervi otpuštaju bivaju preuzeti od nerava koji ih otpušaju radi ponovnog korišćenja (ovo se naziva preuzimanje). Prema mnogim stručnjacima, depresiju izaziva neravnoteža među količinama otpuštenih neurotransmitera. Smatra se da bupropion deluje tako što inhibira preuzimanje neurotransmitera dopamina, serotonina i norepinefrina, dejstvo čiji je rezultat više dopamina, serotonina i norepinefrina dostupnih za prenos drugim nervima. Shodno tome, bupropion je jedinstven utoliko što se njegov glavni efekat ispoljava na dopaminu, efekat koji nemaju SSRI preparati (npr. paroksetin (Paxil®), fluoksetin (Prozac®), sertralin (Zoloft®)) ili triciklični antidepresanti ili TCA preparati (npr. amitriptilin (Elavil®), imipramin (Tofranil®), dezipramin (Norpramin®)).The neurochemical mechanism of the antidepressant effect of bupropion is not well understood. Bupropion does not inhibit monoamine oxidase. Bupropion affects chemicals in the brain that nerves use to send messages to each other. These chemical messages are called neurotransmitters. Neurotransmitters released by nerves are taken up by the nerves releasing them for reuse (this is called uptake). According to many experts, depression is caused by an imbalance between the amounts of released neurotransmitters. Bupropion is thought to work by inhibiting the uptake of the neurotransmitters dopamine, serotonin, and norepinephrine, an effect that results in more dopamine, serotonin, and norepinephrine available for transmission to other nerves. Accordingly, bupropion is unique in that its main effect is exerted on dopamine, an effect that SSRI drugs (eg, paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®)) or tricyclic antidepressants or TCA drugs (eg, amitriptyline (Elavil®), imipramine (Tofranil®), desipramine (Norpramin®)).
Wellbutrin® i VVellbutrin® SR se koriste za obuzdavanje depresije. Zyban® je odobren kao pomoćno sredstvo za pacijente koji žele da prestanu sa pušenjem. VVellbutrin®, formulacija bupropiona sa trenutnim otpuštanjem, dozira se tri puta dnevno, poželjno sa po 6 ili više sati između doza. Za pacijente kojima je potrebno više od 300 mg bupropiona dnevno, nijedna doza ne bi trebalo da prevazilazi 150 mg. Ovo zahteva davanje tableta 4 puta dnevno, sa najmanje 4 sata između doza. Formulacija sa trenutnim otpuštanjem ima za rezultat da se više od 75% bupropiona otupsti u sredinu u kojoj se rastvara za 45 minuta, a jedan od glavnih propratnih efekata bupropiona je pojava napada, koji su delimično izgleda čvrsto povezani sa trenutnim otpuštanjem bupropiona u sistem. Shodno tome, razvijeni su proizvodi sa retard režimom otpuštanja, da bi se izbegla pojava napada.Wellbutrin® and Wellbutrin® SR are used to treat depression. Zyban® is approved as an aid for patients who want to quit smoking. Wellbutrin®, an immediate-release formulation of bupropion, is dosed three times daily, preferably with 6 or more hours between doses. For patients requiring more than 300 mg of bupropion per day, no single dose should exceed 150 mg. This requires giving the tablets 4 times a day, with at least 4 hours between doses. The immediate-release formulation results in more than 75% of bupropion being released into the medium where it dissolves within 45 minutes, and one of the major side effects of bupropion is the occurrence of seizures, which in part seem to be strongly related to the immediate release of bupropion into the system. Consequently, products with a retard release mode were developed to avoid the occurrence of attacks.
Proizvodi sa retard režimom otpuštanja se doziraju dva puta dnevno.Products with a retard mode of release are dosed twice a day.
Uopšte gledano, problem sa lekovima koji zahtevaju režim sa višekratnim doziranjem je disciplinovanost pacijenata i posebno jeIn general, the problem with drugs that require a multiple-dose regimen is patient discipline and is especially so
složen kod individua sa depresijom. Iako su formulacije sa retard režimom otpuštanja pojednostavile doziranje i smanjile problem disciplinovanosti, još uvek ima prostora za dalje pojednostavljenje režima doziranja i dalje poboljšavanje prijemčivosti režima doziranja pacijentu. Razvoj odobrene stabilne formulacije bupropiona sa modifikovanim otpuštanjem za jednokratno dnevno doziranje bio bi napredak u stanju tehnike.complex in individuals with depression. Although delayed-release formulations have simplified dosing and reduced the problem of discipline, there is still room for further simplification of dosing regimens and further improvement of patient acceptability of dosing regimens. The development of an approved stable modified-release formulation of bupropion for once-daily dosing would be an advance in the state of the art.
Formulacije tableta bupropiona sa retard otpuštanjem opisane su u prethodnom stanju tehnike. U patentu U.S. 4,687,660 daje se na uvid javnosti tableta koja je formirana od jezgra i prevlake, gde jezgro sadrži bupropion hidrohlorid zajedno sa ekscipijentom/ekscipijentima i opcionalno agens za pojačanje osmoze i gde prevlaka sadrži vodo-nerastvorni, vodo-propusni polimer koji stvara film (kao što je celuloza acetat), agens za formiranje pora (kao što je fina laktoza i natrijum karbonat) i opcionalno tzv. agens za poboljšanje vodo-propusnosti (kao što je polietilen glikol) i ponovo opcionalni plastifikator.Bupropion sustained-release tablet formulations have been described in the prior art. In U.S. Pat. 4,687,660 discloses a tablet formed from a core and a coating, wherein the core contains bupropion hydrochloride together with excipient(s) and optionally an osmotic enhancing agent and wherein the coating contains a water-insoluble, water-permeable, film-forming polymer (such as cellulose acetate), pore-forming agent (such as fine lactose and sodium carbonate) and optionally the so-called an agent to improve water permeability (such as polyethylene glycol) and again an optional plasticizer.
Patenti U.S. 5,358,970 i 5,427,798 opisuju retard formulaciju bupropion hidrohlorida zasnovanu na tehnologiji matrice. Izraz matrica odnosi se na tabletu u kojoj je lek inkorporiran u ekscipijent koji čini nerazgradivo jezgro koje se naziva matrica.U.S. Patents 5,358,970 and 5,427,798 describe a retard formulation of bupropion hydrochloride based on matrix technology. The term matrix refers to a tablet in which the drug is incorporated into an excipient that forms a non-degradable core called the matrix.
Difuzija leka se odigrava preko ovog jezgra. Kako je bupropion hidrohlorid nestabilan, opisani proizvod u gornja dva patenta zahteva stabilizator da bi se postigla dovoljna stabilnost. Ovaj stabilizator je kiselo jedinjenje, poželjno cistein hidrohlorid. Najveća mana matričnih sistema je da u opštem slučaju ispoljavaju profil otpuštanja prvog reda. To znači da se isprva čestice leka locirane na površini tableteDiffusion of the drug takes place through this core. As bupropion hydrochloride is unstable, the product described in the above two patents requires a stabilizer to achieve sufficient stability. This stabilizer is an acidic compound, preferably cysteine hydrochloride. The biggest disadvantage of matrix systems is that they generally exhibit a first-order release profile. This means that initially the drug particles are located on the surface of the tablet
prve rastvaraju i lek se brzo otpušta. Nakon toga, rastvaraju se i otpuštaju čestice leka koje se nalaze na sve većim rastojanjima od površine tablete, difuzijom iz pora prema spoljašnjosti tablete. Na taj način difuziona udaljenost leka se povećava kako napreduje proces otpuštanja. Normalno je poželjnije da profil otpuštanja bude nultog reda ili približno nultog reda nego prvog reda. Sistem otpuštanja nultog reda obezbeđuje konstantnu brzinu otpuštanja leka u određenom vremenskom intervalu. Koristi se prvenstveno za lekove sa kratkim poluživotom tako da se sa manjim brojem doza mogu održavati konstantni nivoi aktivnog jedinjenja leka u krvi.they first dissolve and the medicine is released quickly. After that, drug particles that are located at increasing distances from the surface of the tablet are dissolved and released, by diffusion from the pores towards the outside of the tablet. In this way, the diffusion distance of the drug increases as the release process progresses. It is normally preferable for the release profile to be zero-order or nearly zero-order than first-order. The zero-order release system provides a constant rate of drug release in a certain time interval. It is used primarily for drugs with a short half-life, so that constant levels of the active drug compound in the blood can be maintained with fewer doses.
Patent US 6,589,553 i međunarodna objava br. WO 02/062299 navodno opisuje formulaciju kapsule za jednokratnu dnevnu dozu sa dve grupe presvučenih dražeja, od kojih svaka otpušta bupropion hidrohlorid na različitim pH. Jedna grupa dražeja je presvučena tako da otpušta lek na pH oko 4,8 i nižim. Očekuje se da se otpuštanje leka iz ove grupe dražeja odigrava u gornjem delu gastrointestinalnog trakta. Druga grupa dražeja je presvučena tako da otpušta lek na pH oko 7 i iznad. Očekuje se da se otpuštanje bupropiona iz ove grupe dražeja odigrava u donjem delu gastrointestinalnog trakta. U jednom od predstavljenih primera, relativna biodostupnost bupropiona preparatu Zyban® bila je samo 40% u smislu odnosa Cmax i samo 80% u smislu odnosa AUC0_jnf. U još jednom od predstavljenih primera, relativna biodostupnost bupropiona preparatu Zyban® bila je samo 48% i 59% u smislu C_av i AUCn inf.US Patent 6,589,553 and International Publication No. WO 02/062299 purportedly describes a once daily dose capsule formulation with two groups of coated dragees, each releasing bupropion hydrochloride at a different pH. One group of dragees is coated so that it releases the drug at a pH of around 4.8 and lower. It is expected that the release of the drug from this group of dragees takes place in the upper part of the gastrointestinal tract. The second group of dragees is coated so that it releases the drug at a pH of around 7 and above. It is expected that the release of bupropion from this group of dragees takes place in the lower part of the gastrointestinal tract. In one of the presented examples, the relative bioavailability of bupropion to Zyban® was only 40% in terms of the Cmax ratio and only 80% in terms of the AUC0_jnf ratio. In another of the presented examples, the relative bioavailability of bupropion to the preparation Zyban® was only 48% and 59% in terms of C_av and AUCn inf.
Reference dalje opisuju uvođenje treće grupe nepresvučenih aktivnih dražeja, koje navodno rezultuju u daljoj modifikaciji i poboljšanju otpuštanja bupropiona. Na osnovu vremenskog profila koncentracije u plazmi prikazanog na crtežima 3 i 4 ovih referenci nije sasvim očigledno da bi uvođenje nepresvučenih aktivnih dražeja rezultovalo u formulaciji za jednokratni dnevni bioekvivalent (referentni proizvod je Zyban6). Takođe, nijedna od dve pomenute reference ne prikazuje podatke o stabilnosti leka.The references further describe the introduction of a third group of uncoated active dragees, which allegedly result in further modification and enhancement of bupropion release. Based on the plasma concentration-time profile shown in Figures 3 and 4 of these references, it is not entirely obvious that the introduction of uncoated active dragees would result in a once-daily bioequivalent formulation (the reference product is Zyban6). Also, none of the two mentioned references show data on the stability of the drug.
Patent US 6,033,686 opisuje tabletu sa retard otpuštanjem koja ne sadrži stabilizator niti agens za formiranje pora, a sadrži jezgro koje se suštinski sastoji od bupropion hidrohlorida, veziva i lubrikanta; i prevlaku koja sadrži vodo-nerastvorni, vodo-propusni polimer koji formira film, plastifikator i vodorastvorni polimer. Proizvod koji proizilazi iz patenta '686 je proizvod koji se uzima dva puta dnevno.US Patent 6,033,686 describes a delayed-release tablet that contains no stabilizer or pore-forming agent and contains a core consisting essentially of bupropion hydrochloride, a binder and a lubricant; and a coating comprising a water-insoluble, water-permeable, film-forming polymer, a plasticizer, and a water-soluble polymer. The product derived from the '686 patent is a twice daily product.
Oba patenta US 6,096,341 i 6,143,327 odnose se na retard formulaciju bupropion hidrohlorida. Patent'341 obezbeđuje tabletu sa retard otpuštanjem, bez stabilizatora i bez agenasa za formiranje pora, koja sadrži jezgro koje se suštinski sastoji od bupropion hidrohlorida, veziva i lubrikanta; i prevlaku koja se suštinski sastoji od vodo- nerastvornog, vodo-propusnog polimera koji formira film, plastifikatora i vodorastvornog polimera. Patent '327 obezbeđuje tabletu sa retard otpuštanjem, bez stabilizatora i bez agenasa za stvaranje pora, koja sadrži jezgro koje se suštinski sastoji od bupropion hidrohlorida, veziva i lubrikanta; i prevlaku za kontrolisano otpuštanje koja se suštinski sastoji od vodo-nerastvornog, vodo-propusnog polimera koji formira film, plastifikatora i vodorastvornog polimera i drugu prevlaku koja se suštinski sastoji od metakrilnog polimera i plastifikatora. Formulacija opisana u patentu '327, međutim, nije u skladu sa smernicama FDA za bioekvivalenciju (vidi primer 8 u ovom tekstu).Both US patents 6,096,341 and 6,143,327 relate to a retard formulation of bupropion hydrochloride. The '341 patent provides a stabilizer-free, pore-forming agent-free, sustained-release tablet containing a core consisting essentially of bupropion hydrochloride, a binder and a lubricant; and a coating consisting essentially of a water-insoluble, water-permeable, film-forming polymer, a plasticizer, and a water-soluble polymer. The '327 patent provides a stabilizer-free, pore-forming agent-free, sustained-release tablet containing a core consisting essentially of bupropion hydrochloride, a binder, and a lubricant; and a controlled release coating consisting essentially of a water-insoluble, water-permeable film-forming polymer, a plasticizer, and a water-soluble polymer, and a second coating consisting essentially of a methacrylic polymer and a plasticizer. The formulation described in the '327 patent, however, does not comply with FDA guidelines for bioequivalence (see Example 8 herein).
Trenutno nema odobrene formulacije bupropiona zaThere is currently no approved formulation of bupropion for
jednokratnu dnevnu dozu dostupne na tržištu. Shodno tome, postoji potreba za stabilnom formulacijom bupropiona ili njegove farmaceutski prihvatljive soli u obliku bioekvivalenta za jednokratno dnevno doziranje.single daily dose available on the market. Accordingly, there is a need for a stable formulation of bupropion or a pharmaceutically acceptable salt thereof in bioequivalent form for once daily dosing.
DEFINICIJEDEFINITIONS
"Formulacije sa modifikovanim otpuštanjem" definisane su od strane USP kao one čije su karakteristike otpuštanja leka u vremenu i/ili mestu odabrane tako da postignu terapijske ciljeve ili ciljeve pogodnosti koje konvencionalne formulacije ne nude. Formulacija sa produženim otpuštanjem omogućava dvostruko smanjenje učestalosti doziranja ili poboljšanje disciplinovanosti pacijenta ili performansi terapije. USP smatra da su izrazi kontrolisano otpuštanje, sporo otpuštanje i retard otpuštanje međusobno zamenjivi sa izrazom produženo otpuštanje. Shodno tome, izrazi "modifikovano otpuštanje", "kontrolisano otpuštanje", "sporo otpuštanje", "produženo otpuštanje" i "retard otpuštanje" u ovom tekstu se koriste tako da su međusobno zamenjivi."Modified-release formulations" are defined by the USP as those whose time and/or site drug release characteristics are selected to achieve therapeutic goals or goals of convenience that conventional formulations do not offer. The sustained-release formulation allows for a two-fold reduction in dosing frequency or improved patient compliance or therapy performance. USP considers the terms controlled release, slow release and retard release to be interchangeable with the term sustained release. Accordingly, the terms "modified release," "controlled release," "slow release," "extended release," and "delayed release" are used interchangeably herein.
Izraz "farmaceutski prihvatljiva so bupropionina" obuhvata soli koje pacijent fiziološki toleriše. Takve soli se tipično spravljaju od neorganskih kiselina ili baza i/ili organskih kiselina ili baza. Primeri takvih kiselina i baza su dobro poznati prosečnom stručnjaku u oblasti. Ovaj pronalazak konkretno razmatra upotrebu bupropion hidrohlorida, iako je upotreba drugih farmaceutski prihvatljivih soli takođe obuhvaćena opsegom pronalaska. Izraz "delotvorna količina" onako kako se ovde koristi znači "farmaceutski delotvorna količina". "Farmaceutski delotvorna količina" je količina farmaceutski prihvatljive soli bupropiona, koja je dovoljna da izazove značajan biološki odgovorThe term "a pharmaceutically acceptable salt of bupropion" includes salts that are physiologically tolerated by the patient. Such salts are typically made from inorganic acids or bases and/or organic acids or bases. Examples of such acids and bases are well known to one of ordinary skill in the art. The present invention specifically contemplates the use of bupropion hydrochloride, although the use of other pharmaceutically acceptable salts is also within the scope of the invention. The term "effective amount" as used herein means "a pharmaceutically effective amount". "Pharmaceutically effective amount" is an amount of a pharmaceutically acceptable salt of bupropion that is sufficient to elicit a significant biological response
kada se da pacijentu. Treba prihvatiti da precizna terapijska doza zavisi od starosti i stanja pacijenta i od prirode stanja koje treba tretirati i predstavlja konačno diskreciono pravo konkretnog lekara.when given to the patient. It should be accepted that the precise therapeutic dose depends on the age and condition of the patient and on the nature of the condition to be treated and represents the final discretion of the particular physician.
Izraz "barijera za vlagu" onako kako se ovde koristi je ona barijera koja sprečava ili usporava apsorpciju vlage. Poznato je da je bupropion hidrohlorid visoko higroskopan i, kao takav, srazmerno je nestabilan i podložan razgradnji u toku vremena, naročito pod uslovima visoke vlažnosti. Srazmera komponenata barijere za vlagu i količina barijere koja se nanese na prevlaku za kontrolisano otpuštanje takva je da ova barijera protiv vlage ne spada pod USP definiciju i zahtev za enteričnu prevlaku. Poželjno je da se barijera za vlagu sastoji od enteričnog i/ili akrilnog polimera, poželjno akrilnog polimera, opcionalno plastifikatora i pojačavača permeacije. Pojačavač permeacije je hidrofilna supstanca koja omogućava vodi da prođe bez fizičkog narušavanja prevlake. Barijera za vlagu može dodatno sadržati druge konvencionalne inertne ekscipijente, koji mogu poboljšati obradu u organizmu ovde opisane formulacije sa modifikovanim otpuštanjem.The term "moisture barrier" as used herein is a barrier that prevents or retards the absorption of moisture. Bupropion hydrochloride is known to be highly hygroscopic and, as such, relatively unstable and subject to degradation over time, particularly under high humidity conditions. The ratio of the moisture barrier components and the amount of barrier applied to the controlled release coating is such that this moisture barrier does not fall within the USP definition and requirement for an enteric coating. Preferably, the moisture barrier consists of an enteric and/or acrylic polymer, preferably an acrylic polymer, optionally a plasticizer and a permeation enhancer. A permeation enhancer is a hydrophilic substance that allows water to pass through without physically disrupting the coating. The moisture barrier may additionally contain other conventional inert excipients, which may improve the processing in the body of the modified release formulation described herein.
Izraz "ukupne nečistoće" označava sve proizvode razgradnje koji su rezultat razgradnje bupropion hidrohlorida. "Proizvodi razgradnje" obuhvataju one navedene na stranici 281, 26. izdanja USPThe term "total impurities" means all degradation products resulting from the degradation of bupropion hydrochloride. "Decomposition products" include those listed on page 281, 26th edition USP
i bilo koje druge proizvode razgradnje koji se mogu pojaviti kao maksimumi na hromatogramu za vreme hromatografske analize.and any other degradation products that may appear as peaks on the chromatogram during chromatographic analysis.
Tablete sa modifikovanim otpuštanjem prema predmetnom pronalasku koje sadrže bioekvivalent tabletama preparata VVellbutrin ® ili Zyban®/Wellbutrin®SR. Izraz "bioekvivalent" označava odustvo značajne razlike u brzini i stepenu do kojeg aktivni sastojak ili aktivniModified-release tablets according to the present invention containing bioequivalent tablets of the preparation VWellbutrin ® or Zyban ® / Wellbutrin ® SR. The term "bioequivalent" means the absence of a significant difference in the rate and degree to which the active ingredient or active
entitet u farmaceutskim ekvivalentima ili farmaceutskim alternativama postaje dostupan na mestu delovanja leka kada se daje u istoj molarnoj dozi pod sličnim uslovima u odgovarajuće postavljenoj studiji. Tamo gde postoji namerna razlika u brzini (npr. u određenim formulacijama sa produženim otpuštanjem), izvesni farmaceutski ekvivalenti ili alternative mogu biti smatrani bioekvivalentnim ukoliko nema značajne razlike u stepenu u kojem aktivni sastojak ili entitet svakog od proizvoda postaje dostupan na mestu delovanja leka. Ovo se odnosi samo na slučajeve kada je razlika u brzini pri kojoj aktivni sastojak ili entitet postaje dostupan na mestu delovanja leka namerna i odražava se u predloženom načinu označavanja, nije suštinska za postizanje delotvornih koncentracija leka pri hroničnom korišćenju i smatra se medicinski beznačajnom za lek.the entity in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action of the drug when given in the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in speed (eg, in certain sustained-release formulations), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the rate at which the active ingredient or entity of each product becomes available at the drug's site of action. This applies only to cases where the difference in the rate at which the active ingredient or entity becomes available at the site of action of the drug is intentional and reflected in the proposed labeling method, is not essential to achieve effective concentrations of the drug in chronic use, and is considered medically insignificant for the drug.
KRATAK OPIS PRONALASKABRIEF DESCRIPTION OF THE INVENTION
Predmetni pronalazak se odnosi na tabletu farmaceutski prihvatljive soli bupropioa, poželjno bupropion hidrohlorida, sa modifikovanim otpuštanjem. Prednost tableta sa modifikovanim otpuštanjem prema pronalasku koju ne obezbeđuje prethodno stanje tehnike u vidu na tržištu dostupnih tableta preparata VVellbutrin® ili Zyban®/Wellbutrin® SR jeste u tome što tablete sa modifikovanim otpuštanjem omogućavaju režim jednokratnog dnevnog uzimanja, što su bioekvivalentne na tržištu dostupnim tabletama prethodnog stanja tehnike i ne pokazuju efekat hrane.The subject invention relates to a tablet of a pharmaceutically acceptable salt of bupropion, preferably bupropion hydrochloride, with a modified release. An advantage of the modified-release tablets according to the invention, which is not provided by the prior art in the form of commercially available Wellbutrin® or Zyban®/Wellbutrin® SR tablets, is that the modified-release tablets allow a once-daily regimen, which are bioequivalent to commercially available tablets. prior art and do not show a food effect.
U skladu sa jednim aspektom predmetnog pronalaska obezbeđuje se tableta sa modifikovanim otpuštanjem, koja sadrži (i) jezgro koje sadrži delotvornu količinu farmaceutski prihvatljive soli bupropiona, vezivo, lubrikant; i (ii) prevlaku za kontrolisano otpuštanjeIn accordance with one aspect of the present invention, there is provided a modified release tablet, comprising (i) a core containing an effective amount of a pharmaceutically acceptable salt of bupropion, a binder, a lubricant; and (ii) a controlled release coating
koja okružuje pomenuto jezgro; i (iii) barijeru za vlagu koja okružuje pomenutu prevlaku za kontrolisano otpuštanje; i; gde je tableta sa modifikovanim otpuštanjem bioekvivalentna i ispoljava profil rastvaranja takav da posle oko 2 časa nije više od 20%, poželjno oko 2% do oko 18%, poželjnije oko 4% do oko 8%, a najpoželjnije oko 5% sadržaja bupropion hidrohlorida otpušteno, posle oko 4 časa, oko 15% do oko 45%, poželjno oko 21% do oko 37%, poželjnije oko 28% do oko 34%, a najpoželjnije oko 32% sadržaja bupropion hidrohlorida je otpušteno, posle oko 8 časova, oko 40% do oko 90%, poželjno oko 60% do oko 85%, poželjnije oko 68% do oko 74%, a najpoželjnije oko 74% sadržaja bupropion hidrohlorida je otpušteno, a posle oko 16 časova nije manje od oko 80%, poželjno ne manje od oko 93%, poželjnije ne manje od oko 96%, a najpoželjnije ne manje od oko 99% sadržaja bupropion hidrohlorida je otpušteno.which surrounds said core; and (iii) a moisture barrier surrounding said controlled release coating; and; wherein the modified release tablet is bioequivalent and exhibits a dissolution profile such that after about 2 hours no more than 20%, preferably about 2% to about 18%, more preferably about 4% to about 8%, and most preferably about 5% of the bupropion hydrochloride content is released , after about 4 hours, about 15% to about 45%, preferably about 21% to about 37%, more preferably about 28% to about 34%, and most preferably about 32% of the bupropion hydrochloride content is released, after about 8 hours, about 40 % to about 90%, preferably about 60% to about 85%, more preferably about 68% to about 74%, and most preferably about 74% of the bupropion hydrochloride content is released, and after about 16 hours not less than about 80%, preferably not less of about 93%, more preferably not less than about 96%, and most preferably not less than about 99% of the bupropion hydrochloride content is released.
U jednom načinu primene barijera za vlagu ne funkcioniše kao enterična prevlaka kao što je to definisano u USP testu, što zahteva tabletu prevučenu enteričnom prevlakom, kada se stavi u 0,1N HCI na 1 čas, da ukupna oslobođena količina leka ne prelazi 10%, a da oslobođena količina leka nije manja od 75% posle 45 minuta u puferu na pH 6,8.In one application, the moisture barrier does not function as an enteric coating as defined in the USP test, which requires an enteric-coated tablet, when placed in 0.1N HCl for 1 hour, that the total amount of drug released does not exceed 10%. and that the released amount of drug is not less than 75% after 45 minutes in buffer at pH 6.8.
U jednom načinu primene predmetnog pronalaska,In one way of applying the subject invention,
farmaceutski prihvatljiva so bupropiona je prisutna sa najmanje oko 94% težinskih od težine suvog jezgra. Poželjno je da tableta sa modifikovanim otpuštanjem prema predmetnom pronalasku sadrži od oko 50 mg do oko 450 mg bupropion hidrohlorida. Najpoželjnije je da tablete prema pronalasku sadrže oko 150 mg ili 300 mg bupropion hidrohlorida.a pharmaceutically acceptable salt of bupropion is present at least about 94% by weight of the weight of the dry core. Preferably, the modified release tablet of the present invention contains from about 50 mg to about 450 mg of bupropion hydrochloride. It is most preferable that the tablets according to the invention contain about 150 mg or 300 mg of bupropion hydrochloride.
U još jednom načinu primene predmetnog pronalaska, prisutna količina veziva je poželjno od oko 1% do oko 6% i poželjnije oko 3% težinskih od težine suvog jezgra. Poželjno je da je vezivo polivinil alkohol.In another embodiment of the present invention, the amount of binder present is preferably from about 1% to about 6% and more preferably about 3% by weight of the weight of the dry core. Preferably, the binder is polyvinyl alcohol.
U još jednom načinu primene predmetnog pronalaska, prisutna količina lubrikanta je poželjno od oko 1% do oko 6% i poželjnije oko 3% težinskih od težine suvog jezgra. Lubrikanti koji su korisni za tablete predmetnog pronalaska mogu biti odabrani iz grupe koja se sastoji od gliceril behenata, stearinske kiseline, hidrogenizovanih biljnih ulja i bilo koje njihove kombinacije. Željeni lubrikant je gliceril behenat.In another embodiment of the present invention, the amount of lubricant present is preferably from about 1% to about 6% and more preferably about 3% by weight of the weight of the dry core. Lubricants useful for the tablets of the present invention may be selected from the group consisting of glyceryl behenate, stearic acid, hydrogenated vegetable oils, and any combination thereof. The preferred lubricant is glyceryl behenate.
U još jednom načinu primene predmetnog pronalaska, prevlaka za kontrolisano otpuštanje se suštinski sastoji od vodo- nerastvornog vodo-propusnog polimera koji formira film i prisutna količina može da varira od oko 35% do oko 60% težinskih od težine suve prevlake za kontrolisano otpuštanje. Poželjno je da je količina prisutnog vodo-nerastvornog vodo-propusnog polimera koji formira film oko 50% težinskih suve prevlake za kontrolisano otpuštanje za dozu od 150 mg i oko 45% težinskih suve prevlake za kontrolisano otpuštanje za dozu od 300 mg. Vodo-nerastvorni vodo-propusni polimeri koji formiraju film mogu biti odabrani iz grupe koja se sastoji od celuloznih etara, celuloznih estara, polivinil alkohola i bilo koje njihove kombinacije. Poželjni vodo-nerastvorni vodo-propusni polimeri koji formiraju film su etil celuloze i mogu biti odabrani iz grupe koja se sastoji od etil celuloze klase PR 100, etil celuloze klase PR 20 i bilo koje njihove kombinacije. Poželjni vodo-nerastvorni vodo-propusni polimer koji formira film jeste etil celuloza klase PR 100.In yet another embodiment of the present invention, the controlled release coating consists essentially of a water-insoluble water-permeable film-forming polymer and the amount present may vary from about 35% to about 60% by weight of the dry controlled release coating. Preferably, the amount of water-insoluble water-permeable film-forming polymer present is about 50% by weight of the dry controlled release coating for the 150 mg dose and about 45% by weight of the dry controlled release coating for the 300 mg dose. The water-insoluble water-permeable film-forming polymers may be selected from the group consisting of cellulose ethers, cellulose esters, polyvinyl alcohol, and any combination thereof. Preferred water-insoluble water-permeable film-forming polymers are ethyl celluloses and may be selected from the group consisting of PR 100 grade ethyl cellulose, PR 20 grade ethyl cellulose, and any combination thereof. The preferred water-insoluble water-permeable film-forming polymer is PR 100 grade ethyl cellulose.
U još jednom načinu primene predmetnog pronalaska, plastifikator je prisutan u količini od oko 6% do oko 30%, poželjnije oko 12% težinskih od težine suve prevlake za kontrolisano otpuštanje. Plastifikatori korisni za tablete prema predmetnom pronalasku mogu se odabrati iz grupe koja se sastoji od poliola, organskih estara, ulja/glicerida i bilo koje njihove kombinacije. Željeni plastifikator je polietilen glikol 1450.In another embodiment of the present invention, the plasticizer is present in an amount of about 6% to about 30%, more preferably about 12% by weight of the dry controlled release coating weight. Plasticizers useful for the tablets of the present invention may be selected from the group consisting of polyols, organic esters, oils/glycerides, and any combination thereof. The preferred plasticizer is polyethylene glycol 1450.
U još jednom načinu primene predmetnog pronalaska, količina prisutnog vodorastvornog polimera može varirati od oko 25% do oko 50% težinskih od težine suve prevlake za kontrolisano otpuštanje. Poželjno je da je vodorastvorni polimer prisutan u količini oko 43% težinskih od težine prevlake za kontrolisano otpuštanje. Vodorastvorni polimer se može odabrati iz grupe koja se sastoji od polivinilpirolidona, hidroksipropil metilceluloze, hidroksipropil celuloze i bilo koje njihove kombinacije. Željeni vodorastvorni polimer je polivinilpirolidon.In yet another embodiment of the present invention, the amount of water soluble polymer present may vary from about 25% to about 50% by weight of the dry controlled release coating weight. Preferably, the water soluble polymer is present in an amount of about 43% by weight of the weight of the controlled release coating. The water-soluble polymer may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and any combination thereof. The preferred water-soluble polymer is polyvinylpyrrolidone.
U još jednom načinu primene predmetnog pronalaska, odnos vodo-nerastvorni vodo-propusni polimer koji formira film:plastifikator:vodorastvorni polimer za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem od 150 mg prema pronalasku može da varira od oko 3:1:4 do oko 5:1:3, uz željeni odnos 4:1:3.In yet another embodiment of the present invention, the ratio of water-insoluble water-permeable film-forming polymer:plasticizer:water-soluble polymer for the modified-release bupropion hydrochloride 150 mg tablet of the invention may vary from about 3:1:4 to about 5: 1:3, with the desired ratio 4:1:3.
U još jednom načinu primene predmetnog pronalaska, odnos vodo-nerastvorni vodo-propusni polimer koji formira film:plastifikator:vodorastvorni polimer za tabletu bupropionIn another embodiment of the present invention, the ratio of water-insoluble water-permeable film-forming polymer:plasticizer:water-soluble polymer for bupropion tablet
hidrohlorida sa modifikovanim otpuštanjem od 300 mg prema pronalasku može da varira od oko 7:2:6 do oko 19:5:18, uz željeni odnos 13:4:12.modified release hydrochloride 300 mg according to the invention may vary from about 7:2:6 to about 19:5:18, with a preferred ratio of 13:4:12.
U još jednom načinu primene predmetnog pronalaska, dodatna težina koja se dobija presvlačenjem jezgra tablete prevlakom za kontrolisano otpuštanje može da varira od 3% do oko 30% u odnosu na težinu suvog jezgra tablete. Za dozu od 150 mg tablete prema predmetnom pronalasku, dobitak težine može da varira od oko 13% do oko 16% od težine suvog jezgra tablete, uz željeni dobitak težine od oko 15% od težine suvog jezgra tablete. Za dozu od 300 mg tablete sa modifikovanim otpuštanjem prema predmetnom pronalasku, dobitak težine ostvaren nanošenjem prevlake za kontrolisano otpuštanje može da varira od oko 8% do oko 10% od težine suvog jezgra tablete, uz željeni dobitak težine od oko 9% od težine suvog jezgra tablete.In another embodiment of the present invention, the additional weight obtained by coating the tablet core with the controlled release coating can vary from 3% to about 30% relative to the weight of the dry tablet core. For a 150 mg tablet dose according to the present invention, the weight gain can vary from about 13% to about 16% of the dry tablet core weight, with a desired weight gain of about 15% of the dry tablet core weight. For a 300 mg dose of a modified release tablet according to the present invention, the weight gain achieved by applying the controlled release coating can vary from about 8% to about 10% of the dry core weight of the tablet, with a desired weight gain of about 9% of the dry core weight tablets.
U još jednom načinu primene predmetnog pronalaska, barijera za vlagu sadrži enterični i/ili akrilni polimer, plastifikator i pojačavao permeacije i prisutan je u odnosu oko 13:2:5. Enterični i/ili akrilni polimer je poželjno akrilni polimer, koji je opet poželjno da bude kopolimer metakrilne kiseline dostupan na tržištu kao Eudragit® L 30 D-55. Iako prisutna količina kopolimera metakrilne kiseline može da varira od oko 30% do oko 90% težinskih od težin suve barijere za vlagu, poželjno je da je prisutna količina kopolimera metakrilne kiseline oko 66% težine suve barijere za vlagu.In another embodiment of the present invention, the moisture barrier comprises an enteric and/or acrylic polymer, a plasticizer and a permeation enhancer and is present in a ratio of about 13:2:5. The enteric and/or acrylic polymer is preferably an acrylic polymer, which again is preferably a methacrylic acid copolymer available on the market as Eudragit® L 30 D-55. Although the amount of methacrylic acid copolymer present can vary from about 30% to about 90% by weight of the weight of the dry moisture barrier, it is preferred that the amount of methacrylic acid copolymer present is about 66% of the weight of the dry moisture barrier.
U još jednom načinu primene predmetnog pronalaska, plastifikator može biti odabran iz grupe koja se sastoji od poliola, organskih estara, ulja/glicerida i bilo koje njihove kombinacije. ŽeljeniIn yet another way of applying the present invention, the plasticizer can be selected from the group consisting of polyols, organic esters, oils/glycerides, and any combination thereof. Desired
plastifikator za upotrebu u barijeri za vlagu je kombinacija poliola i organskog estra. Željeni poliol u ovoj kombinaciji je polietilen glikol 1450, uz trietil citrat kao željeni organski estar. Odnos organskog estra prema poliolu poželjno je da bude 1:2. Poželjno je da plastifikator bude prisutan u količini od oko 1% do oko 30%, a poželjnije oko 10% težinskih od težine suve barijere za vlagu.plasticizer for use in moisture barrier is a combination of polyol and organic ester. The desired polyol in this combination is polyethylene glycol 1450, with triethyl citrate as the desired organic ester. The ratio of organic ester to polyol is preferably 1:2. The plasticizer is preferably present in an amount of from about 1% to about 30%, more preferably about 10% by weight of the dry moisture barrier weight.
U još jednom načinu primene predmetnog pronalaska, pojačavaš permeacije je hidrofilna supstanca i može biti odabrana iz grupe koja se sastoji od silicijum dioksida, koloidnog silicijuma, laktoze, hidrofinih polimera, natrijum hlorida, aluminijum oksida, koloidnog aluminijum oksida, silicijum dioksida, mikrokristalne celuloze i bilo koje njihove kombinacije. Pojačavaš permeacije je poželjno silicijum dioksid i prisutan je u količini odo oko 20% do oko 40%, a poželjno oko 25% težinskih od težine suve barijere za vlagu.In another way of applying the present invention, the permeation enhancer is a hydrophilic substance and can be selected from the group consisting of silica, colloidal silica, lactose, hydrophilic polymers, sodium chloride, aluminum oxide, colloidal aluminum oxide, silica, microcrystalline cellulose and any combination thereof. The permeation enhancer is preferably silicon dioxide and is present in an amount of from about 20% to about 40%, preferably about 25% by weight of the weight of the dry moisture barrier.
U još jednom načinu primene predmetnog pronalaska, barijera za vlagu se nanosi tako da dobitak težine posle nanošenja barijere za vlagu ne iznosi više od oko 6%, a poželjno je ne više od oko 2,5% težine suve tablete kako za tablete sa modifikovanim otpuštanjem prema predmetnom pronalasku od 150 mg tako i za one od 300 mg.In another embodiment of the present invention, the moisture barrier is applied so that the weight gain after application of the moisture barrier is no more than about 6%, preferably no more than about 2.5% of the dry tablet weight as for modified release tablets according to the subject invention of 150 mg as well as for those of 300 mg.
U još jednom načinu primene predmetnog pronalaska, tableta sa modifikovanim otpuštanjem prema pronalasku obezbeđuje stabilnu formulaciju bupropion hidrohlorida tako da najmanje oko 95%, a poželjno je najmanje oko 97,5% i čak 98,5% ili čak 99%, bupropionIn another embodiment of the present invention, the modified release tablet of the invention provides a stable formulation of bupropion hydrochloride such that at least about 95%, and preferably at least about 97.5% and even 98.5% or even 99%, of the bupropion
hidrohlorida ostaje stabilno posle oko 12 meseci čuvanja na 25°C ±hydrochloride remains stable after about 12 months of storage at 25°C ±
2°C/60%Rel.Vlaž. ± 5%Rel.Vlaž.2°C/60%Rel.Humidity. ± 5%Rel.Humidity.
U još jednom načinu primene predmetnog pronalaska, tableta sa modifikovanim otpuštanjem prema pronalasku obezbeđuje stabilnu formulaciju bupropion hidrohlorida tako da najmanje oko 95%, a poželjno je najmanje oko 97,5% i čak 98,5% ili čak 99%, bupropionIn another embodiment of the present invention, the modified release tablet of the invention provides a stable formulation of bupropion hydrochloride such that at least about 95%, and preferably at least about 97.5% and even 98.5% or even 99%, of the bupropion
hidrohlorida ostaje stabilno posle oko 18 meseci čuvanja na 25°C ± 2°C/60%Rel.Vlaž. ± 5%Rel.Vlaž.hydrochloride remains stable after about 18 months of storage at 25°C ± 2°C/60%Rel.Humidity. ± 5%Rel.Humid.
U još jednom načinu primene predmetnog pronalaska, tablete bupropion hidrohlorida pronalaska su bioekvivalentne kako tabletama VVellbutrin® tako i tabletama Zyban®/Wel!butrin® SR i ne pokazuju efekat hrane.In another embodiment of the present invention, bupropion hydrochloride tablets of the invention are bioequivalent to both Wellbutrin® and Zyban®/Wel!butrin® SR tablets and show no food effect.
U još jednom aspektu pronalaska, barijera za vlagu suštinski sprečava ili usporava apsorbovanje vlage u tabletu, čime se povećava stabilnost bupropion hidrohlorida.In yet another aspect of the invention, the moisture barrier substantially prevents or slows absorption of moisture into the tablet, thereby increasing the stability of bupropion hydrochloride.
KRATAK OPIS CRTEŽABRIEF DESCRIPTION OF THE DRAWINGS
Predmetni pronalazak će još više biti shvaćen na osnovu sledećih detaljnih opisa sa pozivanjem na sledeće crteže u kojima:The subject invention will be further understood from the following detailed description with reference to the following drawings in which:
Crtež 1A je dijagram koji ilustruje profil rastvaranja tableta bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 150 mg, sa tri različite brzine otpuštanja prema jednom načinu primene predmetnog pronalaska.Figure 1A is a diagram illustrating the dissolution profile of a 150 mg modified release bupropion hydrochloride tablet with three different release rates according to one method of administration of the present invention.
Crtež 1B je dijagram koji iiustruje profil rastvaranja tableta bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 300 mg, sa tri različite brzine otpuštanja prema jednom načinu primene predmetnog pronalaska.Figure 1B is a diagram illustrating the dissolution profile of a 300 mg modified release bupropion hydrochloride tablet with three different release rates according to one method of administration of the present invention.
Crtež 2A je dijagram koji iiustruje statističku analizu sadržaja ukupnih nečistoća korigovanih na faktore relativnog odgovora (RRF) kod tableta bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 150 mg prema jednom načinu primeneFigure 2A is a diagram illustrating the statistical analysis of relative response factor (RRF)-corrected total impurity content of bupropion hydrochloride 150 mg modified-release tablets according to one route of administration.
predmetnog pronalaska čuvanim na 25°C ± 2°C/60%Rel.Vlaž. ± 5%Rel.Vlaž. u HDPE bocama (7 kom 40cc i 30 kom 100cc).subject invention stored at 25°C ± 2°C/60%Rel.Humidity. ± 5%Rel.Humid. in HDPE bottles (7 pcs. 40cc and 30 pcs. 100cc).
Crtež 2B je dijagram koji iiustruje statističku analizu sadržaja ukupnih nečistoća korigovanih na faktore relativnog odgovora (RRF) kod tableta bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 300 mg prema jednom načinu primeneFigure 2B is a plot illustrating the statistical analysis of relative response factor (RRF)-corrected total impurity content of 300 mg bupropion hydrochloride modified-release tablets according to one route of administration.
predmetnog pronalaska čuvanim na 25°C ± 2°C/60%Rel.Vlaž. ± 5%Rel.Vlaž. u HDPE bocama (7 kom 40cc i 30 kom lOOcc).subject invention stored at 25°C ± 2°C/60%Rel.Humidity. ± 5%Rel.Humid. in HDPE bottles (7 pcs. 40cc and 30 pcs. lOOcc).
Crtež 3A je dijagram koji iiustruje srednje koncentracije bupropiona u plazmi u studiji ekvivalentnosti doza posle davanja 2 x 150 mg (q.d., tj. jednom dnevno) i 1 x 300 mg (q.d.) tableta bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.Figure 3A is a graph plotting the mean plasma concentrations of bupropion in a dose equivalence study following administration of 2 x 150 mg (q.d., i.e., once daily) and 1 x 300 mg (q.d.) bupropion hydrochloride modified release tablets according to one method of administration of the invention.
Crtež 3B je dijagram koji iiustruje srednje koncentracije hidroksibupropiona u plazmi u studiji ekvivalentnosti doza posle davanja 2 x 150 mg (q.d., tj. jednom dnevno) i 1 x 300 mg (q.d.) tableta bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.Figure 3B is a graph plotting the mean plasma concentrations of hydroxybupropion in a dose equivalence study following administration of 2 x 150 mg (q.d., i.e., once daily) and 1 x 300 mg (q.d.) bupropion hydrochloride modified-release tablets according to one method of administration of the invention.
Crtež 3C je dijagram koji ilustruje srednje koncentracije bupropion treoamino alkohola u plazmi u studiji ekvivalentnosti doza posle davanja 2 x 150 mg (q.d.) i 1 x 300 mg (q.d.) tableta bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.Figure 3C is a graph illustrating the mean plasma concentrations of bupropion threoamino alcohol in a dose equivalence study following administration of 2 x 150 mg (q.d.) and 1 x 300 mg (q.d.) bupropion hydrochloride modified release tablets according to one method of administration of the invention.
Crtež 3D je dijagram koji ilustruje srednje koncentracijeFigure 3D is a diagram illustrating mean concentrations
bupropion eritroamino alkohola u plazmi u studiji ekvivalentnosti doza posle davanja 2 x 150 mg (q.d.) i 1 x 300 mg (q.d.) tableta bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.plasma bupropion erythroamino alcohol in a dose equivalence study after administration of 2 x 150 mg (q.d.) and 1 x 300 mg (q.d.) modified-release bupropion hydrochloride tablets according to one method of administration of the invention.
Crtež 4A je dijagram koji ilustruje efekat hrane na srednje koncentracije bupropiona u plazmi posle davanja jednokratne doze od 150 mg-ske tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.Figure 4A is a diagram illustrating the effect of food on mean plasma bupropion concentrations following administration of a single dose of a 150 mg bupropion hydrochloride modified release tablet according to one method of administration of the invention.
Crtež 4B je dijagram u kojem se porede srednje koncentracije bupropiona u plazmi prikazane na crtežu 4A sa srednjim koncentracijama bupropiona u plazmi posle davanja jednokratne doze 150 mg tablete Zyban® stanja tehnike.Figure 4B is a graph comparing the mean bupropion plasma concentrations shown in Figure 4A to the mean bupropion plasma concentrations following administration of a single dose of 150 mg prior art Zyban® tablets.
Crtež 4C je dijagram u kojem se porede srednje koncentracije hidroksibupropiona u plazmi posle davanja jednokratne doze 150 mg tablete bupropion hidrohlorida prema jednom načinuFigure 4C is a plot comparing the mean plasma concentrations of hydroxybupropion following administration of a single dose of 150 mg bupropion hydrochloride tablets by one route.
primene pronalaska sa srednjim koncentracijama hidroksibupropiona u plazmi posle davanja jednokratne doze 150 mg tablete Zyban® stanja tehnike.application of the invention with mean concentrations of hydroxybupropion in plasma after administration of a single dose of 150 mg Zyban® tablets of the prior art.
Crtež 4D je dijagram u kojem se porede srednje koncentracije bupropion treoamino alkohola u plazmi posle davanja jednokratne doze 150 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska sa srednjim koncentracijama hidroksibupropiona u plazmi posle davanja jednokratne doze 150 mg tablete Zyban® prethodnog stanja tehnike.Figure 4D is a graph comparing mean plasma concentrations of bupropion threoamino alcohol after administration of a single dose of 150 mg bupropion hydrochloride modified-release tablets according to one method of administration of the invention with mean plasma concentrations of hydroxybupropion after administration of a single dose of 150 mg tablets of the prior art Zyban® .
Crtež 4E je dijagram u kojem se porede srednje koncentracije bupropion eritroamino alkohola u plazmi posle davanja jednokratne doze 150 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska sa srednjim koncentracijama hidroksibupropiona u plazmi posle davanja jednokratne doze 150 mg tablete Zyban® stanja tehnike.Figure 4E is a graph comparing the mean plasma concentrations of bupropion erythroamino alcohol after administration of a single dose of 150 mg bupropion hydrochloride modified-release tablets according to one method of administration of the invention with the mean plasma concentrations of hydroxybupropion after administration of a single dose of 150 mg tablets of the prior art Zyban®.
Crtež 5A je dijagram u kojem se porede efekti hrane na srednje koncentracije bupropiona u plazmi od jednokratne doze 150 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.Figure 5A is a graph comparing the effects of food on mean bupropion plasma concentrations of a single dose of 150 mg bupropion hydrochloride modified release tablet according to one method of administration of the invention.
Crtež 5B je dijagram u kojem se porede efekti hrane na srednje koncentracije hidroksibupropiona u plazmi od jednokratne dnevne doze 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.Figure 5B is a graph comparing the effects of food on mean plasma concentrations of hydroxybupropion from a single daily dose of 300 mg bupropion hydrochloride modified release tablets according to one method of administration of the invention.
Crtež 5C je dijagram u kojem se porede efekti hrane na srednje koncentracije bupropion treoamino alkohola u plazmi od jednokratne dnevne doze 300 mg tablete bupropion hidrohlorida saFigure 5C is a plot comparing the effects of food on mean plasma concentrations of bupropion threoamino alcohol from a single daily dose of 300 mg bupropion hydrochloride tablets with
modifikovanim otpuštanjem prema jednom načinu primene pronalaska.modified release according to one way of applying the invention.
Crtež 5D je dijagram u kojem se porede efekti hrane na srednje koncentracije bupropion treoamino alkohola u plazmi od jednokratne dnevne doze 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska.Figure 5D is a diagram comparing the effects of food on mean plasma concentrations of bupropion threoamino alcohol from a single daily dose of 300 mg bupropion hydrochloride modified release tablets according to one method of administration of the invention.
Crtež 6A je dijagram koji ilustruje srednje ustaljene koncentracije bupropiona u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja.Figure 6A is a graph illustrating the mean steady-state plasma concentrations of bupropion following multiple dosing of a once-daily 300 mg bupropion hydrochloride modified-release tablet according to one embodiment of the invention when administered to a fasting patient.
Crtež 6B je dijagram u kojem se porede srednje ustaljene koncentracije bupropiona u krvnoj plazmi prikazane na crtežu 5A sa srednjim ustaljenim koncentracijama bupropiona u plazmi posle davanja višekratne doze tableta Wellbutrin® stanja tehnike, nakon gladovanja.Figure 6B is a graph comparing the mean steady-state plasma concentrations of bupropion shown in Figure 5A to the mean steady-state plasma concentrations of bupropion after administration of multiple doses of prior art Wellbutrin® tablets, after fasting.
Crtež 6C je dijagram na kojem su upoređene srednje ustaljene koncentracije hidroksibupropiona u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja saFigure 6C is a graph comparing the mean steady-state plasma concentrations of hydroxybupropion following multiple dosing of a once-daily 300 mg bupropion hydrochloride modified-release tablet according to one mode of administration of the invention when administered to a fasting patient with
srednjim ustaljenim koncentracijama hidroksibupropiona posle višekratnog doziranja tabletama VVellbutrin® stanja tehnike pacijentu nakon gladovanja.mean steady-state concentrations of hydroxybupropion after repeated dosing with state-of-the-art Wellbutrin® tablets to the patient after fasting.
Crtež 6D je dijagram na kojem su upoređene srednje ustaljene koncentracije bupropion treoamino alkohola u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja sa srednjim ustaljenim koncentracijama bupropion treoamino alkohola posle višekratnog doziranja tabletama VVellbutrin® stanja tehnike pacijentu nakon gladovanja.Figure 6D is a graph comparing the mean steady-state plasma concentrations of bupropion threoamino alcohol following multiple dosing of a once-daily 300 mg modified-release tablet of bupropion hydrochloride according to one method of administration of the invention when administered to a fasting patient with the mean steady-state concentrations of bupropion threoamino alcohol following multiple dosing. state-of-the-art VWellbutrin® tablets to the patient after fasting.
Crtež 6E je dijagram na kojem su upoređene srednje ustaljene koncentracije bupropion eritroamino alkohola u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja sa srednjim ustaljenim koncentracijama bupropion eritroamino alkohola posle višekratnog doziranja tabletama VVellbutrin® stanja tehnike pacijentu nakon gladovanja.Figure 6E is a graph comparing the mean steady-state plasma concentrations of bupropion erythroamino alcohol following multiple dosing of a once-daily 300 mg modified-release tablet of bupropion hydrochloride according to one method of administration of the invention when administered to a fasting patient with the mean steady-state concentrations of bupropion erythroamino alcohol following multiple dosing. state-of-the-art VWellbutrin® tablets to the patient after fasting.
Crtež 7 A je dijagram koji ilustruje srednje ustaljene koncentracije bupropiona u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja.Figure 7A is a graph illustrating the mean steady-state plasma concentrations of bupropion following multiple dosing of a once-daily 300 mg bupropion hydrochloride modified-release tablet according to one embodiment of the invention when administered to a fasting patient.
Crtež 7B je dijagram na kojem su upoređene srednje ustaljene koncentracije bupropiona u krvnoj plazmi prikazane na crtežu 7A sa srednjim ustaljenim koncentracijama buproiona u krvnoj plazmi posle višekratnog doziranja tabletama 150 mg (b.i.d., tj. dva puta dnevno) Zyban® prethodnog stanja tehnike pacijentu nakon gladovanja.Figure 7B is a graph comparing the mean steady-state bupropion plasma concentrations shown in Figure 7A to the mean steady-state buproion plasma concentrations following multiple dosing of 150 mg (b.i.d., twice daily) prior art Zyban® tablets to a fasted patient. .
Crtež 7C je dijagram na kojem su upoređene srednje ustaljene koncentracije hidroksibupropiona u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja sa srednjim ustaljenim koncentracijama hidroksibupropiona u krvnoj plazmi posle višekratnog doziranja tabletama 150 mg (b.i.d., tj. dva puta dnevno) Zyban® prethodnog stanja tehnike pacijentu nakon gladovanja.Figure 7C is a graph comparing the mean steady-state plasma concentrations of hydroxybupropion following multiple dosing of a once-daily 300 mg modified-release tablet of bupropion hydrochloride according to one method of administration of the invention when administered to a fasting patient with the mean steady-state plasma concentrations of hydroxybupropion following multiple dosing with the tablets. 150 mg (b.i.d., i.e., twice daily) of prior art Zyban® to the patient after fasting.
Crtež 7D je dijagram na kojem su upoređene srednje ustaljene koncentracije bupropion treoamino alkohola u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja sa srednjim ustaljenim koncentracijama bupropion treoamino alkohola u krvnoj plazmi posle višekratnog doziranja tabletama 150 mg (b.i.d.) Zyban® stanja tehnike pacijentu nakon gladovanja.Figure 7D is a graph comparing mean steady-state plasma concentrations of bupropion threoamino alcohol following multiple dosing of a once-daily 300 mg bupropion hydrochloride modified-release tablet according to one method of administration of the invention when administered to a fasting patient with mean steady-state plasma concentrations of bupropion threoamino alcohol. after repeated dosing with tablets of 150 mg (b.i.d.) Zyban® prior art to the patient after fasting.
Crtež 7E je dijagram na kojem su upoređene srednje ustaljene koncentracije bupropion eritroamino alkohola u krvnoj plazmi posle višekratnog doziranja jednodnevne 300 mg tablete bupropionFigure 7E is a graph comparing the mean steady-state concentrations of bupropion erythroamino alcohol in blood plasma after repeated dosing of a once-daily 300 mg tablet of bupropion
hidrohlorida sa modifikovanim otpuštanjem prema jednom načinu primene pronalaska kada se daje pacijentu nakon gladovanja sa srednjim ustaljenim koncentracijama bupropion eritroamino alkohola u krvnoj plazmi posle višekratnog doziranja tabletama 150 mg (b.i.d.) Zyban® stanja tehnike pacijentu nakon gladovanja.modified release hydrochloride according to one method of administration of the invention when administered to a post-fasted patient with mean steady-state plasma concentrations of bupropion erythroamino alcohol after repeated dosing with 150 mg (b.i.d.) prior art Zyban® tablets to a post-fasted patient.
DETALJNI OPIS PRONALASKADETAILED DESCRIPTION OF THE INVENTION
Ovde opisani pronalazak odnosi se na tabletu sa modifikovanim otpuštanjem koja ima jezgro koje sadrži farmaceutski prihvatljivu so bupropiona i konvencionalne ekscipijente, okruženo prevlakom za kontrolisano otpuštanje, koja kontroliše otpuštanje farmaceutski prihvatljive soli bupropiona i barijeru za vlagu koja okružuje prevlaku za kontrolisano otpuštanje. Tableta sa modifikovanim otpuštanjem prema pronalasku je bioekvivalentna.The invention described herein relates to a modified release tablet having a core containing a pharmaceutically acceptable bupropion salt and conventional excipients, surrounded by a controlled release coating that controls the release of the pharmaceutically acceptable bupropion salt and a moisture barrier surrounding the controlled release coating. The modified release tablet according to the invention is bioequivalent.
1. Jezgro1. Core
Jezgro tablete sa modifikovanim otpuštanjem sadrži delotvornu količinu farmaceutski prihvatljive soli bupropiona, vezivo i lubrikant, a može sadržavati i druge konvencionalne inertne ekscipijente. Prisutna količina aktivnog teka može da varira od oko 50% do oko 90% težinskih od težine suve tablete, a poželjno od oko 70% do oko 90% težinskih od težine suve tablete. Poželjno je da je farmaceutski prihvatljiva so bupropiona bupropion hidrohlorid. Tableta sadrži količinu bupropion hidrohlorida koja može da varira od oko 50 mg do oko 450 mg. Poželjno je da tableta sadrži 150 mg ili 300 mg bupropion hidrohlorida. Za tabletu sa dozom od 150 mg bupropionThe modified-release tablet core contains an effective amount of a pharmaceutically acceptable salt of bupropion, a binder and a lubricant, and may contain other conventional inert excipients. The amount of active ingredient present can vary from about 50% to about 90% by weight of the weight of the dry tablet, and preferably from about 70% to about 90% by weight of the weight of the dry tablet. Preferably, the pharmaceutically acceptable salt of bupropion is bupropion hydrochloride. The tablet contains an amount of bupropion hydrochloride that can vary from about 50 mg to about 450 mg. Preferably, the tablet contains 150 mg or 300 mg of bupropion hydrochloride. For a tablet with a dose of 150 mg bupropion
hidrohlorid predstavlja oko 78% težinskih od težine suve tablete. Za dozu od 300 mg bupropion hidrohlorid predstavlja oko 83% težinskih od težine suve tablete. I u slučaju tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku u dozi od 150 mg i od 300 mg, prisutna količina bupropion hidrohlorida je oko 94% težinskih od težine suvog jezgra, za svaku dozu.hydrochloride represents about 78% by weight of the weight of the dry tablet. For a dose of 300 mg, bupropion hydrochloride represents about 83% by weight of the weight of the dry tablet. Both in the case of the 150 mg and 300 mg modified release bupropion hydrochloride tablets of the invention, the amount of bupropion hydrochloride present is about 94% by weight of the dry core weight, for each dose.
Vezivo (ponekad tzv. adheziv) se dodaje u smešu punioca za lek, da bi se osiguralo da granule i tablete mogu biti oblikovane tako da imaju zahtevanu mehaničku otpronost. Veziva se mogu dodavati formulaciji na različite načine: (1) kao suvi prah koji se mesa sa ostalim sastojcima pre mokre aglomeracije, (2) kao rastvor, koji se koristi kao tečnost za aglomeraciju za vreme mokre aglomeracije i pominje se kao vezivo rastvora i (3) kao suvi prah, koji se meša sa ostalim sastojcima pre sabijanja. U ovom obliku vezivo se naziva suvo vezivo. Veziva rastvora se u opštem slučaju smatraju najdelotvornijim, te je ovo najčešći način inkorporiranja veziva u granule. Ovde korišćeno vezivo je u obliku veziva rastvora. Neograničavajući primeri veziva koja su korisna za jezgro obuhvataju vodorastvorne polimere kao što je modifikovani škrob, želatin, polivinilpirolidon, derivati celuloze (kao što je npr. hidroksipropil metilceluloza (HPMC) i hidroksipropil celuloza (HPC)) i polivinil alkohol. Prisutna količina veziva može da varira od oko 0,5% do oko 15% težinskih od težine suve tablete, poželjno od oko 1% do oko 6% težinskih od težine suve tablete, a najpoželjnije oko 3% težinskih od težine suve tablete. I u slučaju tableta sa dozom od 150 mg i od 300 mg, prisutna količina veziva može biti od 1% do oko 6% težinskih od težine svakog suvog jezgra, a poželjnije 3% težinskih od težine svakog suvog jezgra. Željeno vezivo je polivinil alkohol.A binder (sometimes called an adhesive) is added to the drug filler mixture to ensure that the granules and tablets can be shaped to have the required mechanical resistance. Binders can be added to the formulation in various ways: (1) as a dry powder that is mixed with other ingredients before wet agglomeration, (2) as a solution, which is used as an agglomeration fluid during wet agglomeration and is referred to as a solution binder and ( 3) as a dry powder, which is mixed with other ingredients before compaction. In this form, the binder is called a dry binder. Solution binders are generally considered the most effective, and this is the most common way of incorporating binders into granules. The binder used here is in the form of a solution binder. Non-limiting examples of binders useful for the core include water-soluble polymers such as modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (such as, for example, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)), and polyvinyl alcohol. The amount of binder present may vary from about 0.5% to about 15% by weight of the dry tablet weight, preferably from about 1% to about 6% by weight of the dry tablet weight, and most preferably about 3% by weight of the dry tablet weight. In the case of both the 150 mg and 300 mg tablets, the amount of binder present may be from 1% to about 6% by weight of each dry core, more preferably 3% by weight of each dry core. The preferred binder is polyvinyl alcohol.
Veziva se dodaju farmaceutskim formulacijama da bi se osiguralo da oblikovanje tablete i izbacivanje mogu da se ostvare uz nisko trenje između čvrstog proizvoda i zida kalupa. Visoko trenje za vreme tabletiranja može da izazove ozbiljne probleme, uključujući nedovoljan kvalitet tablete (cepanje ili čak raspadanje tableta za vreme izbacivanja i vertikalne ogrebotine na ivicama tablete) i čak zaustavljanje proizvodnje. Shodno tome, lubrikanti se dodaju skoro svim formulacijama tableta, uključujući formulacijama tableta bupropion hidrohlorida koje su ovde opisane. Neograničavajući primeri lubrikanata korisnih za jezgro obuhvataju gliceril behenat, stearinsku kiselinu, hidrogenizovana biljna ulja (kao što je hidrogenizovano ulje konopljinog semena (Sterotex®), hidrogenizovano sojino ulje (Sterotex ® HM) i hidrogenizovano sojino ulje sa ricinusovim voskom (Sterotex® K), stearil alkohol, leucin i polietilen glikol (MT 4000 i viša). Poželjno je daje lubrikant gliceril behenat. Prisutna količina lubrikanta može da varira od oko 1% do oko 5% težinskih od težine suve tablete, poželjno od oko 2% do oko 3% težinskih od težine suve tablete, a najpoželjnije oko 2,5% težinskih od težine suve tablete. Za tablete sa modifikovanim otpuštanjem prema pronalasku sa dozom od 150 mg i 300 mg, prisutna količina lubrikanta je 2,5% težinskih od težine suve tablete, a poželjno je od oko 1% do oko 6% težinskih od težine suvog jezgra, još poželjnije oko 3% težinskih od težine suvog jezgra, za obe doze.Binders are added to pharmaceutical formulations to ensure that tablet forming and ejection can be accomplished with low friction between the solid product and the mold wall. High friction during tableting can cause serious problems, including insufficient tablet quality (tearing or even disintegration of the tablet during ejection and vertical scratches on tablet edges) and even production stoppage. Accordingly, lubricants are added to almost all tablet formulations, including the bupropion hydrochloride tablet formulations described herein. Non-limiting examples of lubricants useful for the core include glyceryl behenate, stearic acid, hydrogenated vegetable oils (such as hydrogenated hemp seed oil (Sterotex®), hydrogenated soybean oil (Sterotex® HM), and hydrogenated soybean oil with castor wax (Sterotex® K), stearyl alcohol, leucine and polyethylene glycol (MT 4000 and above). Preferably the lubricant is glyceryl behenate. The amount of lubricant present can vary from about 1% to about 5% by weight of the dry tablet weight, preferably from about 2% to about 3% by weight of the dry tablet weight, and most preferably about 2.5% by weight of the dry tablet weight For modified release tablets according to the invention with a dose of 150 mg and 300 mg, the amount of lubricant present is 2.5% by weight of the dry tablet weight, and preferably from about 1% to about 6% by weight of the dry kernel weight, more preferably about 3% by weight of the dry kernel weight, for both dosages.
Na ovom stupnju, formulacija jezgra je formulacija sa trenutnim otpuštanjem, što rezultuje u 100% rastvaranju bupropion hidrohlorida u okviru 1 časa (podaci nisu prikazani). Idealno, jezgro sadrži samo delotvornu farmaceutsku količinu farmaceutski prihvatljive soli bupropiona, vezivo, poželjno polivinil alkonol i lubrikant, poželjno gliceril behenat. Međutim, ako je potrebno, u formulaciju jezgra seAt this stage, the core formulation is an immediate release formulation, resulting in 100% dissolution of bupropion hydrochloride within 1 hour (data not shown). Ideally, the core contains only a pharmaceutically effective amount of a pharmaceutically acceptable salt of bupropion, a binder, preferably polyvinyl alkanol, and a lubricant, preferably glyceryl behenate. However, if necessary, it is included in the formulation
uvode dodatni inertni ekscipijenta koji služe ciljevima pronalaska. Ovi dodatni inertni ekscipijenti se mogu dodati da bi olakšali spravljanje i/ili poboljšali prihvatljivost konačne dozne formulacije bupropion hidrohlorida sa modifikovanim otpuštanjem za pacijenta, kako je ovde opisano. Dodatni inertni ekscipijenti su dobro poznati prosečnom stručnjaku i mogu se naći u odgovarajućoj literaturi, na primer u "Priručniku za farmaceutske ekscipijente". IMeograničavajući primeri takvih ekscipijenata obuhvataju laktozu sušenu raspršivanjem, sorbitol, manitol i derivate celuloze.introduce additional inert excipients that serve the purposes of the invention. These additional inert excipients may be added to facilitate the preparation and/or improve patient acceptability of the modified-release bupropion hydrochloride final dosage formulation as described herein. Additional inert excipients are well known to one of ordinary skill in the art and can be found in the appropriate literature, for example in the "Handbook of Pharmaceutical Excipients". Non-limiting examples of such excipients include spray-dried lactose, sorbitol, mannitol, and cellulose derivatives.
Željeno je da granule, koje treba sabiti da bi se oblikovalo jezgro tablete sa modifikovanim otpuštanjem prema ovde opisanom pronalasku, budu izrađene mokrim postupkom granulacije. Suštinski, mokra granulacija podrazumeva mešanje praha (aktivnog leka) konvekcijom u prisustvu tečnosti (veziva rastvora) nakon čega sledi sušenje. Za formiranje granula koje će na kraju biti sabijene u jezgra tableta, bupropion hidrohlorida se najpre granuliše, poželjno sa vezivom rastvora, u granulatoru, poželjno ali ne obavezno u granulatoru sa fluidizovanim slojem kao što je npr. granulator sa fluidizovanim slojem koji proizvodi Glatt (Nemačka) ili Aeromatic (Švajcarska). Vezivo, poželjno polivinil alkohol, se najpre rastvara ili disperguje u pogodnom rastvaraču, poželjno vodi. Vezivo rastvora se zatim raspršuje odozgo preko leka u granulatoru, poželjno granulatoru sa fluidizovanim slojem. Alternativno, granulisanje se može sprovesti u konvencionalnom mikseru ili mikseru visoke brzine. Ukoliko je potrebno, inertni ekscipijenti kao što je na primer punilac mogu se smešati sa bupropion hidrohloridom pre koraka granulisanja.It is desired that the granules, which are to be compacted to form the modified release tablet core of the invention described herein, are made by a wet granulation process. Essentially, wet granulation involves mixing the powder (active drug) by convection in the presence of a liquid (solution binder) followed by drying. To form granules that will eventually be compacted into tablet cores, bupropion hydrochloride is first granulated, preferably with a binder solution, in a granulator, preferably but not necessarily in a granulator with a fluidized bed, such as, for example, fluidized bed granulator manufactured by Glatt (Germany) or Aeromatic (Switzerland). The binder, preferably polyvinyl alcohol, is first dissolved or dispersed in a suitable solvent, preferably water. The binder solution is then sprayed from above over the drug in a granulator, preferably a fluidized bed granulator. Alternatively, granulation can be carried out in a conventional mixer or a high speed mixer. If necessary, inert excipients such as a filler may be mixed with bupropion hydrochloride prior to the granulation step.
Formirane granule se potom suše, a zatim prosejavaju pre zamešavanja sa lubrikantom. Poželjno je da se osušene granule prosejavaju kroz sito sa 1,4 mm mesom. Prosejane granule se zatim zamešavaju sa lubrikantom i, ako je neophodno, bilo kojim drugim inetrnim ekscipijentima, što može poboljšati obradu u organizmu tableta sa modifikovanim otpuštanjem prema pronalasku.The formed granules are then dried and then sieved before mixing with the lubricant. It is preferable to sift the dried granules through a 1.4 mm sieve. The sieved granules are then mixed with a lubricant and, if necessary, any other inert excipients, which can improve the processing in the body of the modified release tablets according to the invention.
Zamešavanje granula sa lubrikantom i ako je neophodno bilo kakvim dodatnim inertnim ekscipijentima, kao na primer sredstvom za klizenje, može se izvesti u V-blenderu ili bilo kakvoj drugoj pogodnoj aparaturi za mešanje. Sredstva za klizenje poboljšavaju točivost praha. Ovo je posebno važno za vreme proizvodnje tableta pri visokim vrzinama proizvodnje i u toku direktnog sabijanja. Međutim, kako je zahtev za dovoljnu točivost visok, granulaciji se često dodaje i sredstvo za klizenje pre tabletiranja. Zamešane granule se potom sabijaju u tabletu i u daljem tekstu će se kao takve nazivati jezgro tablete.Mixing of the granules with the lubricant and if necessary any additional inert excipients, such as a glidant, can be done in a V-blender or any other suitable mixing apparatus. Gliding agents improve powder flowability. This is especially important during tablet production at high production speeds and during direct compression. However, as the requirement for sufficient pourability is high, a glidant is often added to the granulation before tabletting. The mixed granules are then compressed into a tablet and will be referred to as the tablet core in the following text.
Jezgra tableta se mogu dobiti korišćenjem standardnih tehnika i opreme koje su dobro poznate prosečnom stručnjaku. Idealno, ali ne obavezno, jezgra tableta se dobijaju pomoću rotacione prese (koja se takođe naziva stupnjevita presa) na kojoj su montirani odgovarajući pritiskivači.Tablet cores can be obtained using standard techniques and equipment well known to one of ordinary skill in the art. Ideally, but not necessarily, the tablet cores are obtained by means of a rotary press (also called a step press) fitted with suitable presses.
2. Prevlake tableta2. Tablet coatings
Jezgra tableta se prevlače u dva stupnja. Prevlaka za kontrolisano otpuštanje se nanosi direktno na površinu jezgara tableta i služi za kontrolisanje otpuštanja farmaceutski prihvatljive soli bupropiona. Barijera za vlagu se nanosi direktno na površinu prevlake za kontrolisano otpuštanje da bi sprečila ili usporila apsropciju vlage.The tablet cores are coated in two stages. The controlled release coating is applied directly to the surface of the tablet cores and serves to control the release of the pharmaceutically acceptable salt of bupropion. A moisture barrier is applied directly to the surface of the controlled release coating to prevent or slow the absorption of moisture.
2.1 Prevlaka za kontrolisano otpuštanje2.1 Controlled release coating
Prevlaka za kontrolisano otpuštanje je polupropusna prevlaka koja se sastoji od vodo-nerastvornog vodo-propusnog polimera koji formira film, plastifikatora i vodorastvornog polimera.A controlled release coating is a semi-permeable coating consisting of a water-insoluble water-permeable film-forming polymer, a plasticizer, and a water-soluble polymer.
Neograničavajući primeri vodo-nerastvornih vodo-propusnih polimera koji formiraju film korisni za prevlaku za kontrolisano otpuštanje obuhvataju celulozne etre, celulozne estre i polivinil alkohol. Željeni vodo-nerastvorni vodo-propusni polimeri koji formiraju film su etil celuloze, a mogu biti odabrane iz grupe koja se sastoji od etil celuloze klase PR100, etil celuloze klase PR20 i bilo koje njihove kombinacije. Etil celuloza klase PR100 je željeni vodo-nerastvorni vodo-propusni polimer koji formira film. Količina vodo-nerastvornog vodo-propusnog polimera koji formira film može da varira od oko 1% do oko 8% težinskih od težine suve tablete, a poželjno od oko 2% do oko 6% težinskih od težine suve tablete. Za 150 mg dozu tableta bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku, količina vodo-nerastvornog vodo-propusnog polimera koji formira film može da varira od oko 3% do oko 6% težinskih od težine suve tablete. Poželjno je da vodo-nerastvorni vodo-propusni polimer koji formira film bude prisuatn u količini oko 6,3% težinskih od težine suve tablete. U odnosu na samu prevlaku za kontrolisano otpuštanje, količina vodo-nerastvornog vodo-propusnog polimera koji formira film može da varira od oko 35% do oko 60% težinskih od težine suve prevlake za kontrolisano otpuštanje. Poželjno je da količina vodo- nerastvornog vodo-propusnog polimera bude 50% težinskih od težine suve prevlake za kontrolisanje propuštanje. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem sa dozom od 300 mg prema pronalasku, količina vodo-nerastvornog vodo-propusnogpolimera koji formira film može da varira od oko 2% do oko 5% težinskih od težine suve tablete. Poželjno je da količina vodonerastvornog vodo-propusnog polimera koji formira film bude oko 3,6% težinskih od težine suve tablete. U odnosu na samu prevlaku za kontrolisano otpuštanje, vodo-nerastvorni vodo-propusni polimer koji formira film je prisutan u količini 45% težinskih od težine suve prevlake za kontrolisano otpuštanje.Non-limiting examples of water-insoluble water-permeable film-forming polymers useful for a controlled release coating include cellulose ethers, cellulose esters, and polyvinyl alcohol. Preferred water-insoluble water-permeable film-forming polymers are ethyl celluloses, and may be selected from the group consisting of PR100 grade ethyl cellulose, PR20 grade ethyl cellulose, and any combination thereof. PR100 grade ethyl cellulose is a preferred water-insoluble water-permeable film-forming polymer. The amount of water-insoluble water-permeable film-forming polymer can vary from about 1% to about 8% by weight of the dry tablet weight, and preferably from about 2% to about 6% by weight of the dry tablet weight. For a 150 mg dose of the modified release bupropion hydrochloride tablets of the invention, the amount of water-insoluble water-permeable film-forming polymer may vary from about 3% to about 6% by weight of the dry tablet weight. Preferably, the water-insoluble water-permeable film-forming polymer is present in an amount of about 6.3% by weight of the dry tablet weight. Relative to the controlled release coating itself, the amount of water-insoluble water permeable film forming polymer can vary from about 35% to about 60% by weight of the dry controlled release coating. It is desirable that the amount of water-insoluble water-permeable polymer be 50% by weight of the weight of the dry coating for controlling leakage. For the 300 mg dose bupropion hydrochloride modified release tablet of the invention, the amount of water-insoluble water-permeable film-forming polymer may vary from about 2% to about 5% by weight of the dry tablet weight. Preferably, the amount of water-insoluble water-permeable film-forming polymer is about 3.6% by weight of the weight of the dry tablet. Relative to the controlled release coating itself, the water-insoluble water-permeable film-forming polymer is present in an amount of 45% by weight of the dry controlled release coating.
Plastifikatori se u opštem slučaju dodaju formulacijama sa prevlakom filma da bi promenili fizička svojstva polimera i učinila ga upotrebljivijim. Količina i izbor plastifikatora doprinosi čvrstoći tablete i može čak da utiče na karakteristike rastvaranja ili razgradnje, kao i na njenu fizičku i hemijsku stabilnost. Jedna važna osobina plastifikatora je njihova sposobnost da prevlaku učine elastičnom i fleksibilnom, čime se smanjuje krtost prevlake. Neograničavajući primeri plastifikatora korisnih za prevlaku za kontrolisano otpuštanje koja je ovde opisana obuhvataju poliole, kao što je polietilen glikol raznih molekulskih težina, organske estre, kao što je dietil ftalat ili trietil citrat, i ulja/giceride kao što su frakcionisano kokosovo ulje ili ricinusovo ulje. Količina plastifikatora za prevlaku za kontrolisano otpuštanje može da varira u iznosu od oko 0,5% do oko 2% težinskih od težine suve tablete.Plasticizers are generally added to film coating formulations to change the physical properties of the polymer and make it more usable. The amount and choice of plasticizer contributes to the strength of the tablet and may even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability. One important property of plasticizers is their ability to make the coating elastic and flexible, thereby reducing the brittleness of the coating. Non-limiting examples of plasticizers useful in the controlled release coating described herein include polyols, such as polyethylene glycol of various molecular weights, organic esters, such as diethyl phthalate or triethyl citrate, and oils/glycerides such as fractionated coconut oil or castor oil. . The amount of plasticizer for the controlled release coating can vary from about 0.5% to about 2% by weight of the dry tablet weight.
Željeni plastifikator je polietilen glikol 1450. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 150 mg prema pronalasku, prisutna količina plastifikatora u prevlaci za kontrolisano otpuštanje može da varira od oko 1% do oko 1,5% težinskih od težine suve tablete. Poželjno je da je plastifikator prisutan u količini oko 1,5% težinskih od težine suve tablete. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 300 mg prema pronalasku, prisutna količina plastifikatora u prevlaci za kontrolisano otpuštanje može da varira od oko 0,5% do oko 2% težinskih od težine suvetablete. I za formu sa dozom od 150 mg i za onu sa dozom od 300 mg poželjno je da je plastifikator prisutan u količini od oko 6% do oko 30% težinskih od težine suve prevlake za kontrolisano otpuštanje, a poželjnije je da količina iznosi 12% težinskih od težine suve prevlake za kontrolisano otpuštanje.The preferred plasticizer is polyethylene glycol 1450. For a 150 mg modified release bupropion hydrochloride tablet of the invention, the amount of plasticizer present in the controlled release coating may vary from about 1% to about 1.5% by weight of the dry tablet. Preferably, the plasticizer is present in an amount of about 1.5% by weight of the weight of the dry tablet. For a 300 mg modified release bupropion hydrochloride tablet according to the invention, the amount of plasticizer present in the controlled release coating may vary from about 0.5% to about 2% by weight of the tablet weight. For both the 150 mg and 300 mg dosage forms, it is preferable that the plasticizer is present in an amount of about 6% to about 30% by weight of the dry controlled release coating weight, and more preferably the amount is 12% by weight of dry coating weight for controlled release.
Neograničavajući primeri vodorastvornih polimera korisnih za prevlaku za kontrolisano otpuštanje obuhvataju polivinilpirolidon, hidroksipropil metilcelulozu i hidroksipropil celulozu. Željeni vodorastvorni polimer je polivinilpirolidon čija količina može da varira od oko 1,5% do oko 6% težinskih od težine suve tablete. U odnosu na samu prevlaku za kontrolisano otpuštanje, prisutna količina vodorastvornog polimera može da varira od oko 25% do oko 55% težinskih od težine suve prevlake sa kontrolisanim otpuštanjem. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 150 mg prema pronalasku, prisutna količina vodorastvornog polimera može da varira od oko 3% do oko 5% težinskih od težine suve tablete ili od oko 25% do oko 50% težinskih od težine suve prevlake za kontrolisano otpuštanje. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 300 mg prema pronalasku, prisutna količina vodorastvornog polimera može da varira od oko 2% do oko 5% težinskih od težine suve tablete i oko 43% težinskih od težine suve prevlake za kontrolisano otpuštanje.Non-limiting examples of water-soluble polymers useful for a controlled release coating include polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. The desired water-soluble polymer is polyvinylpyrrolidone, the amount of which can vary from about 1.5% to about 6% by weight of the dry tablet weight. Relative to the controlled release coating itself, the amount of water soluble polymer present can vary from about 25% to about 55% by weight of the dry controlled release coating. For a 150 mg bupropion hydrochloride modified-release tablet according to the invention, the amount of water-soluble polymer present may vary from about 3% to about 5% by weight of the dry tablet weight or from about 25% to about 50% by weight of the dry coating weight for controlled release. For a 300 mg modified release bupropion hydrochloride tablet according to the invention, the amount of water soluble polymer present may vary from about 2% to about 5% by weight of the dry tablet weight and about 43% by weight of the dry controlled release coating.
Odnos vodo-nerastvorni vodo-propusni polimer koji formira film:plastifikator:vodorastvorni polimer za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 150 mg prema ovde opisanom pronalasku može da varira od oko 3:1:4 do oko 5:1:3. Željeni odnos je oko 4:1:3. Za tabletu bupropion hidrohlorida saThe ratio of water-insoluble water-permeable film-forming polymer:plasticizer:water-soluble polymer for the modified-release bupropion hydrochloride 150 mg tablet of the invention described herein may vary from about 3:1:4 to about 5:1:3. The desired ratio is about 4:1:3. For bupropion hydrochloride tablet with
modifikovanim otpuštanjem u dozi od 300 mg prema ovde opisanom pronalasku odnos vodo-nerastvorni vodo-propusni polimer koji formira film:plastifikator:vodorastvorni polimer može da varira od oko 7:2:6 do oko 19:5:18. Željeni odnos je oko 13:4:12.modified release 300 mg dose according to the invention described herein the ratio of water-insoluble water-permeable film-forming polymer:plasticizer:water-soluble polymer can vary from about 7:2:6 to about 19:5:18. The desired ratio is about 13:4:12.
U opštem slučaju, spravljanje i nanošenje prevlake za kontrolisano otpuštanje izvodi se na sledeći način. Vodo-nerastvorni vodo-propusni polimer koji formira film, poželjno etilceluloza i plastifikator, poželjno polietilen glikol 1450, rastvaraju se u organskom rastvaraču kao što je smeša etil alkohola i izopropil alkohola. Zatim se dodaje plastifikator, poželjno polivinil pirolidon, dok se ne postigne homogena smeša. Dobijeni rastvor za prevlaku za kontrolisano otpuštanje se zatim raspršuje preko jezgara tableta korišćenjem uređaja za presvlačenje tableta, aparatura sa fluidizovanim slojem ili bilo koje pogodne aparature za presvlačanje tableta poznate prosečnom stručnjaku, do postizanja željenog dobitka težine. Jezgra tableta sa prevlakom za kontrolisano otpuštanje se zatim suše pre nego što se nanese barijera za vlagu.In general, the preparation and application of the controlled release coating is carried out as follows. A water-insoluble water-permeable film-forming polymer, preferably ethylcellulose, and a plasticizer, preferably polyethylene glycol 1450, are dissolved in an organic solvent such as a mixture of ethyl alcohol and isopropyl alcohol. Then a plasticizer, preferably polyvinyl pyrrolidone, is added until a homogeneous mixture is achieved. The resulting controlled release coating solution is then sprayed over the tablet cores using a tablet coater, fluidized bed apparatus, or any suitable tablet coating apparatus known to one of ordinary skill in the art, until the desired weight gain is achieved. The controlled-release coated tablet cores are then dried before the moisture barrier is applied.
Prosečan stručnjak će shvatiti da se kontrolisanjem propuštanja može kontrolisati otpuštanje bupropion hidrohlorida i/ili količina prevlake koja se nanosi na jezgra tableta. Propustljivost prevlake sa kontrolisanim otpuštanjem se može menjati variranjem odnosa vodo-nerastvorni vodo-propusni polimer koji formira film:plastifikator:vodorastvorni polimer i/ili količine prevlake koja se nanosi na jezgro tablete. Produženje otpuštanja se u opštem slučaju ostvaruje većom količinom vodo-nerastvornog, vodo-propusnog polimera koji formira film. Propustljivost prevlake za kontrolisano otpuštanje može se takođe menjati dodavanjem drugih ekscipijenata jezgru tablete. Na primer, ukoliko se želi da jezgro tablete sadrži još i ekspanzioni agens, količinu plastifikatora u prevlaci za kontrolisano otpuštanje treba povećati da bi se prevlaka učinila fleksibilnijom, jer bi pritisak ekspanzionog agensa na manje fleksibilnu prevlaku probio prevlaku. Dalje, proporcija vodo-nerastvornog vodo-propusnog polimera koji formira film prema vodorastvornom polimeru takođe možda mora da se menja, zavisno od toga da li se želi profil sa bržim ili sporijim rastvaranjem i/ili otpuštanjem.One of ordinary skill in the art will appreciate that by controlling the leakage, the release of bupropion hydrochloride and/or the amount of coating applied to the tablet cores can be controlled. The permeability of the controlled-release coating can be varied by varying the ratio of water-insoluble water-permeable film-forming polymer:plasticizer:water-soluble polymer and/or the amount of coating applied to the tablet core. Extending the release is generally achieved with a larger amount of water-insoluble, water-permeable film-forming polymer. The permeability of the controlled release coating can also be altered by adding other excipients to the tablet core. For example, if it is desired that the tablet core also contains an expanding agent, the amount of plasticizer in the controlled-release coating should be increased to make the coating more flexible, because the pressure of the expanding agent on the less flexible coating would break the coating. Furthermore, the proportion of water-insoluble water-permeable film-forming polymer to water-soluble polymer may also need to be varied, depending on whether a faster or slower dissolution and/or release profile is desired.
Zavisno od profila rastvaranja ili in vivo otpuštanja, dobitak na težini koji se ostvari presvlačenjem jezgra tablete prevlakom za kontrolisano otpuštanje može da varira od oko 3% do oko 30% težinskih od težine suvog jezgra tablete. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku sa dozom od 150 mg, dobitak težine može da varira od oko 13% do oko 16% težine suvog jezgra tablete. Poželjno je da dobitak težine iznosi oko 15% težine suvog jezgra tablete. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku sa dozom od 300 mg, dobitak težine može da varira od oko 8% do oko 10% težine suvog jezgra tablete. Poželjno je da dobitak težine iznosi oko 9% težine suvog jezgra tablete.Depending on the dissolution or in vivo release profile, the weight gain achieved by coating the tablet core with a controlled release coating can vary from about 3% to about 30% by weight of the dry tablet core weight. For a modified release bupropion hydrochloride tablet of the invention with a dosage of 150 mg, the weight gain can vary from about 13% to about 16% of the dry core weight of the tablet. It is desirable that the weight gain is about 15% of the weight of the dry core of the tablet. For a modified release bupropion hydrochloride tablet of the invention with a dosage of 300 mg, the weight gain can vary from about 8% to about 10% of the dry core weight of the tablet. Preferably, the weight gain is about 9% of the weight of the dry core of the tablet.
2.2 Barijera za vlagu2.2 Moisture barrier
Barijera za vlagu se nanosi direktno na prevlaku za kontrolisano otpuštanje i sadrži enterični i/ili akrilni polimer, pojačavač permeacije i opcionalno plastifikator.The moisture barrier is applied directly to the controlled release coating and contains an enteric and/or acrylic polymer, a permeation enhancer and optionally a plasticizer.
Poželjno je da enterični polimer bude akrilni polimer. Poželjno je da akrilni polimer bude kopolimer metakrilne kiseline tipa C [poli(metakrilna kiselina, metil metakrilat) 1:1] na tržištu dostupan pod nazivom Eudragit® (npr. Eudragit L 30 D-55). Kopolimer metakrilne kiseline je prisutan u količini koja može varirati od oko 1% do oko 3% težinskih od težine suve tablete i od oko 55% do oko 70% težinskih od težine suve barijere za vlagu. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku sa dozom od 150 mg, kopolimer metakrilne kiseline može da varira od oko 2% do oko 3% težine suve tablete. Poželjno je da prisutna količina kopolimera metakrilne kiseline iznosi oko 2,5% težine suve tablete. U odnosu na samu barijeru za vlagu, prisutna količina kopolimera metakrilne kiseline iznosi od oko 30% do oko 90% težinskih od težine suve barijere za vlagu, a poželjnije iznosi 66% težine suve barijere za vlagu. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku sa dozom od 300 mg, količina kopolimera metakrilne kiseline može da varira od oko 1,5% do oko 3% težine suve tablete. Poželjno je da prisutna količina kopolimera metakrilne kiseline iznosi oko 2% težine suve tablete. U odnosu na samu barijeru za vlagu, prisutna količina kopolimera metakrilne kiseline iznosi od oko 30% do oko 90% težinskih od težine suve barijere za vlagu, a poželjnije iznosi 66% težine suve barijere za vlagu za tabletu sa modifikovanim otpuštanjem prema pronalasku u dozi od 300 mg.Preferably, the enteric polymer is an acrylic polymer. Preferably, the acrylic polymer is a C-type methacrylic acid copolymer [poly(methacrylic acid, methyl methacrylate) 1:1] commercially available under the name Eudragit® (eg, Eudragit L 30 D-55). The methacrylic acid copolymer is present in an amount that can vary from about 1% to about 3% by weight of the dry tablet weight and from about 55% to about 70% by weight of the dry moisture barrier weight. For a 150 mg dose bupropion hydrochloride modified release tablet of the invention, the methacrylic acid copolymer may vary from about 2% to about 3% by weight of the dry tablet. Preferably, the amount of methacrylic acid copolymer present is about 2.5% of the weight of the dry tablet. Relative to the moisture barrier itself, the amount of methacrylic acid copolymer present is from about 30% to about 90% by weight of the weight of the dry moisture barrier, more preferably 66% of the weight of the dry moisture barrier. For a 300 mg dose bupropion hydrochloride modified release tablet of the invention, the amount of methacrylic acid copolymer may vary from about 1.5% to about 3% of the weight of the dry tablet. Preferably, the amount of methacrylic acid copolymer present is about 2% of the weight of the dry tablet. Relative to the moisture barrier itself, the amount of methacrylic acid copolymer present is from about 30% to about 90% by weight of the dry moisture barrier, more preferably 66% by weight of the dry moisture barrier for a modified release tablet according to the invention in a dose of 300 mg.
U struci je poznato da kopolimeri metakrilne kiseline imaju tendenciju da postanu krti, te stoga zahtevaju plastifikator. Neograničvajući primeri plastifikatora korisnih za ovde opisanu prevlaku za kontrolisano otpuštanje obuhvataju poliole, kao što je polietilen glikol raznih molekulskih težina, organske estre, kao što je dietil ftalat ili trietil citrat, i ulja/giceride kao što su frakcionisano kokosovo ulje iliIt is known in the art that methacrylic acid copolymers tend to become brittle and therefore require a plasticizer. Non-limiting examples of plasticizers useful in the controlled release coating described herein include polyols, such as polyethylene glycol of various molecular weights, organic esters, such as diethyl phthalate or triethyl citrate, and oils/glycerides such as fractionated coconut oil or
ricinusovo ulje. Željeni plastifikator sadrži kombinaciju trietil citrata i polietilen glikola 1450. Odnos trietil citrata prema polietilen glikolu 1450 je oko 1:2. Plastifikator je prisutan u količini koja može da varira od oko 0,2% do oko 0,5%, a poželjno od oko 0,2% do oko 0,4% težine suve tablete. Plastifikator je prisutan u iznosu oko 0,35% težine suve tablete za tabletu sa 150 mg i od oko 0,2% do oko 0,4% težine suve tablete za tabletu sa 300 mg. U odnosu na samu barijeru za vlagu, plastifikator je prisutan poželjno od oko 1% do oko 30% težinskih od težine suve barijere za vlagu, a poželjnije u količini oko 10% težinskih od težine suve barijere za vlagu i za 150 mg i za 300 mg tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku. U struci je poznato da, zavisno od nameravane glavne funikcije, ekscipijenti koji će se koristiti u tabletama su podkategorizovani u različite grupe. Međutim, jedan ekscipijent može da utiče na osobine leka ili tablete u celini na niz načina i mnoge supstance korišćenje u formulacijama tableta mogu stoga biti opisane kao multifunkcionalne. Na taj način, polietilen glikol 1450 koji se koristi u kombinaciji plastifikatora za barijeru za vlagu služi ne samo za povećavanje hidrofilnosti barijere za vlagu već i kao sredstvo za klizenje.Castor oil. The desired plasticizer contains a combination of triethyl citrate and polyethylene glycol 1450. The ratio of triethyl citrate to polyethylene glycol 1450 is about 1:2. The plasticizer is present in an amount that can vary from about 0.2% to about 0.5%, and preferably from about 0.2% to about 0.4% of the weight of the dry tablet. The plasticizer is present in an amount of about 0.35% of the dry tablet weight for the 150 mg tablet and from about 0.2% to about 0.4% of the dry tablet weight for the 300 mg tablet. Relative to the moisture barrier itself, the plasticizer is present preferably from about 1% to about 30% by weight of the weight of the dry moisture barrier, and more preferably in an amount of about 10% by weight of the weight of the dry moisture barrier for both 150 mg and 300 mg modified release bupropion hydrochloride tablet according to the invention. It is known in the art that, depending on the intended main function, excipients to be used in tablets are subcategorized into different groups. However, a single excipient can affect the properties of the drug or tablet as a whole in a number of ways and many substances used in tablet formulations can therefore be described as multifunctional. Thus, the polyethylene glycol 1450 used in the moisture barrier plasticizer combination serves not only to increase the hydrophilicity of the moisture barrier but also as a slip agent.
Pored polietilen glikola 1450, pojačavač permeacije takođe deluje kao sredstvo za klizenje, a takođe povećava hidrofilnost barijere za vlagu. Pojačavač permeacije je hidrofilna supstanca i može biti odabrana iz grupe koja se sastoji od silicijum dioksida, koloidnog silicijuma, laktoze, hidrofilnih polimera, natrijum hlorida, aluminijum oksida, koloidnog aluminijum oksida, silicijum dioksida, mikrokristalne celuloze i bilo koje njihove kombinacije. Željeni pojačavač permeacije je silicijum dioksid. Količina pojačavača permeacije može da varira od oko 0,5% do oko 1% težinskih od težine suve tablete i iznosi oko 25% težinskih od težine suve barijere za vlagu. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku u dozi od 150 mg, pojačavaš permeacije je prisutan u količini od oko 0,9% težine suve tablete i od oko 20% do oko 40%, a poželjno oko 25% težinskih od težine suve barijere za vlagu. Za tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku u dozi od 300 mg, pojačavaš permeacije je prisutan u količini koja može da varira od oko 0,5% do oko 1% težine suve tablete, a poželjno je prisutna od oko 20% do oko 40%, a poželjno oko 25% težinskih od težine suve barijere za vlagu. .In addition to polyethylene glycol 1450, the permeation enhancer also acts as a slip agent and also increases the hydrophilicity of the moisture barrier. The permeation enhancer is a hydrophilic substance and may be selected from the group consisting of silica, colloidal silica, lactose, hydrophilic polymers, sodium chloride, aluminum oxide, colloidal aluminum oxide, silica, microcrystalline cellulose, and any combination thereof. The preferred permeation enhancer is silica. The amount of permeation enhancer can vary from about 0.5% to about 1% by weight of the dry tablet weight and is about 25% by weight of the dry moisture barrier weight. For a modified release bupropion hydrochloride tablet according to the invention at a dose of 150 mg, the permeation enhancer is present in an amount of about 0.9% by weight of the dry tablet and from about 20% to about 40%, preferably about 25% by weight of the weight of the dry barrier for moisture. For a modified release bupropion hydrochloride tablet according to the invention at a dose of 300 mg, the permeation enhancer is present in an amount that can vary from about 0.5% to about 1% of the weight of the dry tablet, and is preferably present from about 20% to about 40 %, and preferably about 25% by weight of the weight of the dry moisture barrier. .
Odnos kopolimer metakrilne kiseline:plastifikator:pojačavač permeacije je poželjno da bude 13:2:5.The ratio of methacrylic acid copolymer:plasticizer:permeation enhancer is preferably 13:2:5.
U opštem slučaju, postupak spravljanja i nanošenja barijere za vlagu je sledeći. Najpre se u vodu dodaje plastifikator, poželjno kombinacija polietilen glikola 1450 i trietil citrata i smeša se meša do homogenosti. Kopolimer metakrilne kiseline, poželjno Eudragit® L 30 D-55, se zatim prosejava i dodaje smeši plastifikatora i meša do homogenosti. U odvojenom sudu se pojačavaš permeacije, poželjno silicijum dioksid, rastvara u vodi dok se ne postigne homogena smeša. Zatim se smeša plastifikatora i kopolimera metakrilne kiseline sjedinjuju sa rastvorom pojačavača permeacije i mešaju do homogenosti. Dobijen rastvor barijere za vlagu se zatim raspršuje po jezgrima tableta presvučenim prevlakama za kontrolisano otpuštanje pomoću uređaja za presvlačenje tableta, aparaturom sa fluidizovanim slojem ili bilo kojim pogodnim uređajem za presvlačenje poznatim u struci, dok se ne postigne željeni dobitak težine. Tablete presvučene barijerom za vlagu se zatim suše pre pakovanja.In general, the procedure for making and applying a moisture barrier is as follows. First, a plasticizer is added to the water, preferably a combination of polyethylene glycol 1450 and triethyl citrate, and the mixture is mixed until homogeneous. Methacrylic acid copolymer, preferably Eudragit® L 30 D-55, is then sieved and added to the plasticizer mixture and mixed until homogenous. In a separate vessel, permeation is enhanced, preferably silicon dioxide, dissolved in water until a homogeneous mixture is achieved. Then, the mixture of plasticizer and methacrylic acid copolymer is combined with the permeation enhancer solution and mixed until homogeneous. The resulting moisture barrier solution is then sprayed onto the tablet cores coated with controlled release coatings using a tablet coater, fluidized bed apparatus, or any suitable coating device known in the art, until the desired weight gain is achieved. The moisture barrier coated tablets are then dried before packaging.
Barijera za vlagu se nanosi na jezgro tablete presvučeno prevlakom za kontrolisano otpuštanje tako da dobitak u težini ne iznosi više od oko 6%, a poželjno je ne više od oko 2,5% težine suve tablete kako za 150 mg tako i za 300 mg tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku. Količina barijere za vlagu koja se nanese ne čini ovde opisanu tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem otpornom na stomačnu tečnost niti ima značajan uticaj na karakteristike otpuštanja leka.The moisture barrier is applied to the tablet core coated with a controlled release coating such that the weight gain is no more than about 6%, and preferably no more than about 2.5% of the dry tablet weight for both the 150 mg and 300 mg tablets. modified release bupropion hydrochloride according to the invention. The amount of moisture barrier applied does not render the bupropion hydrochloride modified release tablet described herein resistant to gastric fluid nor does it significantly affect the drug release characteristics.
Barijera za vlagu, onako kako je ovde korišćena, ne funkcioniše kao enterična prevlaka. Iako se kopolimer metakrilne kiseline, Eudragit® L 30 D-55, navodi i koristi u struci kao formulacija enterične prevlake, njena funkcionalnost zavisi od formulacije i od količine nanesenog materijala. Kao što je poznato u struci, enterična prevlaka se nanosi tamo gde lek može biti uništen ili dezaktiviran stomačnim sokovima ili tamo gde lek može da iritira stomačnu sluzokožu. Da bi se zadovoljili zahtevi za enteričnu prevlaku, test koji je opisan u USP (metod A ili B) propisuje da nakon 2 časa u kiseloj sredini (0,1N HCI) nijedna pojedinačna vrednost od najmanje 6 eksperimenata ne pokazuje da je više od 10% aktivnog leka rastvoreno i ne manje od 75% rastvoreno za 45 minuta na pH 6,8. Barijera za vlagu ne zadovoljava ovaj zahtev zbog sledećih razloga, iako kisela sredina ne utiče negativno na bupropion hidrohlorid niti je on iritantan za stomačnu sluzokožu: (1) da bi se ostvario enterični integritet kod filma koji sadrži Eudragit® L 30 D-55 preporučuje se dobitak težine od oko 6% do oko 8% prema suvom polimeru po jedinici doze. Količina čvrstog preparata Eudragit® L 30 D-55 koja se nanosi na jezgro tablete presvučene prevlakom za kontrolisano otpuštanje ne iznosi više od 6%, a poželjno je ne više od 2,5%, (2) ukoliko bi se zahtevao enterični integritet, test rastvaranja za gotov proizvod (tj. jezgra tableta presvučena barijerom za vlagu) ne bi propisivao granicu od 20% na 2 časa i (3) analitički testovi izvedeni na konačnom dvostruko presvučenom proizvodu ukazuju da proizvod ne ispunjava sve zahteve testa kao proizvod sa enteričnom prevlakom onako kako je to definisano USP metodima testiranja. Kako se barijera za vlagu nanosi direktno na prevlaku za kontrolisano otpuštanje, sprovedeni su testovi da bi se utvrdilo da li barijera za vlagu nanesena direktno na jezgra tableta sa trenutnim otpuštanjem funkcioniše kao enterična prevlaka. Testovi pokazuju da posle 1 časa više od 40% bupropion hidrohlorida bude otpušteno iz jezgara tableta u 0,1 N Hcl, te stoga ne potpada pod definiciju USP za enteričnu prevlaku (vidi primer 2). Funkcionalnost barijere za vlagu je takođe bila potvrđena određivanjem sadržaja vlage korišćenjem Karl-Fišerovog (KF) testa pojedinačnih jezgara tableta sa prevlakom za kontrolisano otpuštanje i barijerom za vlagu pod ubrzanim uslovima (40°C ± 2°C/75%Rel.vlaž. ± 5% Rel.vlaž.) u otvorenom staklenom sudu, 10 dana (vidi primer 2). Rezultati pokazuju da je sadržaj vlage za jezgra sa prevlakom za kontrolisano otpuštanje viši nego za jezgra tableta presvučena barijerom za vlagu. Ovi podaci kumulativno ustanovljavaju funkcionalnost barijere za vlagu kao prevlake, koja suštinski sprečava ili usporava apsorpciju vlage i nije enterična prevlaka onako kako je to definisano od strane USP.A moisture barrier as used here does not function as an enteric coating. Although the methacrylic acid copolymer, Eudragit® L 30 D-55, is listed and used in the art as an enteric coating formulation, its functionality depends on the formulation and the amount of material applied. As is known in the art, an enteric coating is applied where the drug may be destroyed or deactivated by gastric juices or where the drug may irritate the gastric mucosa. To meet the requirements for an enteric coating, the test described in the USP (method A or B) stipulates that after 2 hours in an acidic medium (0.1N HCI) no single value from at least 6 experiments shows that more than 10% of the active drug dissolved and not less than 75% dissolved in 45 minutes at pH 6.8. A moisture barrier does not meet this requirement for the following reasons, although an acidic environment does not adversely affect bupropion hydrochloride nor is it irritating to the gastric mucosa: (1) to achieve enteric integrity of a film containing Eudragit® L 30 D-55 is recommended a weight gain of about 6% to about 8% based on dry polymer per unit dose. The amount of Eudragit® L 30 D-55 solid preparation applied to the core of the tablet coated with a controlled release coating is not more than 6%, and preferably not more than 2.5%, (2) if enteric integrity is required, the test dissolution rate for the finished product (ie, moisture barrier coated tablet core) would not dictate the 20% limit at 2 hours and (3) analytical tests performed on the final double-coated product indicate that the product does not meet all test requirements as an enteric-coated product as such as defined by USP test methods. As the moisture barrier is applied directly to the controlled release coating, tests were conducted to determine if the moisture barrier applied directly to the immediate release tablet cores functioned as an enteric coating. Tests show that after 1 hour more than 40% of the bupropion hydrochloride is released from the tablet core in 0.1 N Hcl, and therefore does not fall within the USP definition of enteric coating (see Example 2). The functionality of the moisture barrier was also confirmed by determining the moisture content using the Karl-Fisher (KF) test of single core tablets with a controlled-release coating and a moisture barrier under accelerated conditions (40°C ± 2°C/75%Rel.Hyd. ± 5% RH) in an open glass container, 10 days (see example 2). The results show that the moisture content of cores with a controlled release coating is higher than that of tablet cores coated with a moisture barrier. These data cumulatively establish the functionality of a moisture barrier coating that substantially prevents or retards moisture absorption and is not an enteric coating as defined by the USP.
Tableta prema pronalasku obezbeđuje produženo otpuštanje bupropion hidrohlorida iako nikakav agens za stvaranje pora nije prisutan u formulaciji. Gorepomenuta formulacija takođe obezbeđuje stabilnu formulaciju bupropion hidrohlorida, takvu je da nakon 2 časa ne više od 20%, poželjno je oko 2% do oko 18%, poželjnije oko 4% do oko 8%, a najpoželjnije oko 5% bupropion hidrohlorida otpušteno, nakon 4 časa, oko 20% do oko 45%, poželjno je oko 21% do oko 37%, poželjnije oko 28% do oko 34%, a najpoželjnije oko 32% bupropion hidrohlorida je otpušteno, nakon oko 8 časova, oko 40% do oko 90%, poželjno je oko 60% do oko 85%, poželjnije oko 68% do oko 74%, a najpoželjnije oko 74% bupropion hidrohlorida je otpušteno i nakon 16 časova ne manje od oko 80%, poželjno je ne manje od oko 93%, poželjnije ne manje od oko 96%, a najpoželjnije ne manje od oko 99% bupropion hidrohlorida je otpušteno.The tablet according to the invention provides a sustained release of bupropion hydrochloride although no pore forming agent is present in the formulation. The aforementioned formulation also provides a stable formulation of bupropion hydrochloride, such that after 2 hours no more than 20%, preferably about 2% to about 18%, more preferably about 4% to about 8%, and most preferably about 5% of bupropion hydrochloride released, after 4 hours, about 20% to about 45%, preferably about 21% to about 37%, more preferably about 28% to about 34%, and most preferably about 32% bupropion hydrochloride is released, after about 8 hours, about 40% to about 90%, preferably about 60% to about 85%, more preferably about 68% to about 74%, and most preferably about 74% of bupropion hydrochloride is released and after 16 hours not less than about 80%, preferably not less than about 93% , more preferably not less than about 96%, and most preferably not less than about 99% of the bupropion hydrochloride has been released.
Pozitivan efekat na stabilnost tablete bupropion hidrohlorida sa modifikovanim otpuštanjem po ovde opisanoj formulaciji očigledan je u testovima sprovedenim radi evaluacije ukupnih nečistoća prisutnih i u dozama od 150 mg i od 300 mg u toku 6 meseci pod ubrzanim uslovima (40°C ± 2°C/75%Rel.vlaž. ± 5% Rel.vlaž.) kao i u toku 12 meseci i 18 meseci dugoročne stabilnosti pri 25°C ± 2°C/60% Rel.vlaž. ± 5% Rel.vlaž. Testovi stabilnosti su pokazali smanjene vrednosti (u odnosu na Wellbutrin SR) ukupnih nečistoća u tabletama.A positive effect on the stability of the bupropion hydrochloride modified-release tablet according to the formulation described here is evident in tests conducted to evaluate the total impurities present in both 150 mg and 300 mg doses over 6 months under accelerated conditions (40°C ± 2°C/75 %RH ± 5% RH) as well as during 12 months and 18 months of long-term stability at 25°C ± 2°C/60% RH. ± 5% Rel. humidity Stability tests showed reduced values (compared to Wellbutrin SR) of total impurities in the tablets.
U 7 HDPE boca od 40 cc i 30 boca od 100 cc i za tablete sa modifikovanim otpuštanjem sa dozom od 150 mg i od 300 mg prema pronalasku na primer, ukupne prisutne nečistoće ne bi trebalo da prevazilaze 2,5% težinskih od težine bupropion hidrohlorida u tableti, poželjno je ne više od oko 1,5%, a najpoželjnije ne više od oko 0,6% u toku najmanje 12 meseci dugoročne stabilnosti pri 25°C ± 2°C/60% Rel.vlaž. ± 5% Rel.vlaž. Po isteku 18 meseci dugoročne stabilnosti pri 25°C ± 2°C/60% Rel.vlaž. ± 5% Rel.vlaž., ukupne prisutne nečistoće ne bi trebalo da prevazilaze oko 2,5% težinskih od težine bupropion hidrohlorida u tableti, poželjno je ne više od oko 1,5%, a najpoželjnije ne više od oko 0,7% težinskih od težine bupropion hidrohlorida u tableti. Na taj način, tableta bupropion hidrohlorida prema predmetnom pronalasku sadrži najmanje oko 95% težinskih, poželjnije najmanje 98% ili čak najmanje 99% nerazgrađenog bupropion hidrohlorida posle čuvanja od 12 ili 18 meseci dugoročne stabilnosti pod uslovima vlažnosti i temperature koji se najčešće nalaze u apotekama i ormarima za lekove, tj. sobna temperatura i vlažnost od 35-60% . Na primer, ako tableta u početku sadrži 300 mg bupropion hidrohlorida (deklarisanu količinu) u trenutku spravljanja, nakon jednogodišnjeg čuvanja u tableti će preostati najmanje 285 mg bupropion hidrohlorida, a poželjno je najmanje 294 mg ili više.In 7 HDPE bottles of 40 cc and 30 bottles of 100 cc and for 150 mg and 300 mg modified release tablets according to the invention for example, the total impurities present should not exceed 2.5% by weight of the weight of bupropion hydrochloride in a tablet, preferably not more than about 1.5%, and most preferably not more than about 0.6% during at least 12 months of long-term stability at 25°C ± 2°C/60% RH. ± 5% Rel. humidity After 18 months of long-term stability at 25°C ± 2°C/60% RH. ± 5% Rel.Moisture, the total impurities present should not exceed about 2.5% by weight of the weight of bupropion hydrochloride in the tablet, preferably not more than about 1.5%, and most preferably not more than about 0.7% by weight than the weight of bupropion hydrochloride in a tablet. In this way, the bupropion hydrochloride tablet according to the present invention contains at least about 95% by weight, more preferably at least 98% or even at least 99% of undegraded bupropion hydrochloride after storage of 12 or 18 months of long-term stability under humidity and temperature conditions that are most often found in pharmacies and medicine cabinets, i.e. room temperature and humidity of 35-60%. For example, if a tablet initially contains 300 mg of bupropion hydrochloride (declared amount) at the time of preparation, after one year of storage, at least 285 mg of bupropion hydrochloride will remain in the tablet, preferably at least 294 mg or more.
Sadržaj vlage prema KF i ukupna količina nečistoća bupropion hidrohlorida za tablete sa dozom od 150 mg prema pronalasku pri čuvanju pod ubrzanim uslovima 6 meseci za 7 HDPE boca od 40 cc trebalo bi da ne prevazilazi oko 1%. Ista konfiguracija boca i tableta za dozu od 300 mg čuvane pod istim ubrzanim uslovima trebalo bi da ima sadržaj vlage po KF ne veći od oko 1% i ukupne nečistoće ne više od 0,6% nakon najmanje 6 meseci. Tablete sa 150 mg čuvane u konfiguraciji od 30 FIDPE boca od 100 cc trebalo bi da imaju sadržaj vlage po KF ne veći od oko 1% i ukupne nečistoće ne više od 1,2% nakon najmanje 6 meseci čuvanja pod ubrzanim uslovima. Tablete sa 300 mg koje se čuvaju u istoj konfiguraciji pod istim uslovima isti period vremena treba da imaju sadržaj vlage po KF ne veći od 1% i ukupne nečistoće ne više od oko 0,8%. Kada se čuva u otvorenoj staklenoj šolji, sadržaj vlage po KF za tabletu sa modifikovanim otpuštanjem u dozi od 300 mg prema pronalasku ne bi trebalo da bude veći od oko 0,8% nakon 3 dana, a poželjno je ne više od 0,45% nakon 10 dana kada se čuva pod ubrzanim uslovima. Kada se čuva u hermetički zatvorenim staklenim bocama sadržaj vlage po KF treba da bude ne veći od 0,45% nakon 3 dana, a poželjno je ne veći od 0,4% nakon 10 dana.The moisture content according to KF and the total amount of impurities of bupropion hydrochloride 150 mg tablets according to the invention when stored under accelerated conditions for 6 months for 7 HDPE bottles of 40 cc should not exceed about 1%. The same configuration of bottles and tablets for the 300 mg dose stored under the same accelerated conditions should have a KF moisture content of no more than about 1% and total impurities no more than 0.6% after at least 6 months. The 150 mg tablets stored in a configuration of 30 FIDPE bottles of 100 cc should have a KF moisture content of no more than about 1% and total impurities of no more than 1.2% after at least 6 months of storage under accelerated conditions. 300 mg tablets stored in the same configuration under the same conditions for the same period of time should have a moisture content by KF of no more than 1% and total impurities no more than about 0.8%. When stored in an open glass cup, the moisture content per KF for a 300 mg modified release tablet according to the invention should be no more than about 0.8% after 3 days, preferably no more than 0.45% after 10 days when stored under accelerated conditions. When stored in hermetically sealed glass bottles, the moisture content according to KF should be no higher than 0.45% after 3 days, and preferably no higher than 0.4% after 10 days.
Sledeći primeri ilustruju predmetni pronalazak i nisu namenjeni ograničavanju opsega predmetnog pronalaska.The following examples illustrate the subject invention and are not intended to limit the scope of the subject invention.
PRIMER 1FIRST 1
1. Formulacije tableta sa modifikovanim otpuštanjem1. Modified-release tablet formulations
Tri različite formulacije jezgara su spravljene za svaku od tableta bupropion hidrohlorida sa modifikovanim otpuštanjem, kako za onu sa dozom od 150 mg tako i za onu od 300 mg, kao što je prikazano u tabeli 1:Three different core formulations were made for each of the bupropion hydrochloride modified-release tablets, both the 150 mg and 300 mg, as shown in Table 1:
Najpre se zagreje voda do 60 ± 5°C. Zatim se vezivo (polivinil alkohol) rastvara u vodi do homogenosti, a zatim propusti kroz sito sa mesom od 0,7 mm i ostavi da se ohladi do temperature ne više od oko 30°C. Bupropion hidrohlorid se postavi u gornju komoru za raspršavanje aparature sa fluidizovanim slojem, kao stoje na primer aparatura sa fluidizovanim slojem Glatt GPCG1. Vezivo rastvora (npr. polivinil alkoholni rastvor) se rasprši preko bupropion hidrohlorida, sa procesnim parametrima prikazanim u tabeli 2:First, the water is heated to 60 ± 5°C. Then the binder (polyvinyl alcohol) is dissolved in water until homogenous, then passed through a 0.7 mm sieve and allowed to cool to a temperature of no more than about 30°C. Bupropion hydrochloride is placed in the upper nebulization chamber of a fluidized bed apparatus, such as the Glatt GPCG1 fluidized bed apparatus. A binder solution (e.g. polyvinyl alcohol solution) is sprayed over the bupropion hydrochloride, with the process parameters shown in Table 2:
Kada je granulacija završena, granule se ostave da se osuše a zatim se hlade na temperaturu ne višu od oko 35°C. Granule bupropion hidrohlorida se zatim propuštaju kroz sito sa mešom od 1,4 mm.When the granulation is finished, the granules are left to dry and then cooled to a temperature no higher than about 35°C. The bupropion hydrochloride granules are then passed through a 1.4 mm mesh screen.
Lubrikant (gliceril behenat) zamešava se zatim zajedno sa prosejanim granulama u V-blenderu dok se smeša ne izjednači. Dobijena smeša se sabija u jezgra tableta korišćenjem rotacione tabletne prese (Manesty Unipress) sa prosečnom tvrdoćom od oko 8 Sc do oko 25 Sc i prosečnom debljinom od oko 3,9 mm do oko 4,5 mm za jezgra tableta od 150 mg i prosečnom tvrdoćom od oko 12 Sc do oko 33 Sc i prosečnom debljinom od oko 4,8 mm do oko 5,4 mm za jezgra tableta od 300 mg. Mrvljivost jezgara tableta za obe tabletne doze je ne veća od 0,8%. Zatim se jezgra tableta presvlače prevlakom za kontrolisano otpuštanje prema formulacijama prikazanim u tabeli 3:The lubricant (glyceryl behenate) is then mixed together with the sieved granules in a V-blender until the mixture is uniform. The resulting mixture is compressed into tablet cores using a rotary tablet press (Manesty Unipress) with an average hardness of about 8 Sc to about 25 Sc and an average thickness of about 3.9 mm to about 4.5 mm for 150 mg tablet cores and an average hardness from about 12 Sc to about 33 Sc and an average thickness of about 4.8 mm to about 5.4 mm for the 300 mg tablet cores. The friability of the tablet cores for both tablet dosages is no higher than 0.8%. The tablet cores are then coated with a controlled release coating according to the formulations shown in Table 3:
Plastifikator (polietilen glikol 1450), a zatim se vodonerastvorni vodopropusni polimer koji formira film (etilceluloza 100) dodaje delu smeše denaturisanog etil alkohola i izopropil alkohola. Nakon mešanja postepeno se dodaje vodorastvorni polimerA plasticizer (polyethylene glycol 1450) and then a water-insoluble water-permeable film-forming polymer (ethylcellulose 100) are added to a portion of the mixture of denatured ethyl alcohol and isopropyl alcohol. After mixing, the water-soluble polymer is gradually added
gornjoj smeši da bi se izbegio formiranje grudvi. Rastvor se mesa do homogenosti. Ostatak denaturisanog etil alkohola i izopropil alkohola se zatim dodaje smeši za prevlaku i mešanje se nastavlja dok se ne postigne homogen rastvor. Zatim se rastvor za prevlaku propušta kroz homogenizator DeBee Homogenizer (veličina mlaznice 7, procesni pritisak 8500 ± 2000 psi i pozadinski pritisak 1000 ± 250 psi). Homogenizovani rastvor za prevlaku se zatim raspršuje po jezgrima za tablete u uređaju za presvlačenje tableta (O'Hara 36 Side Vent) sa procesnim parametrima prikazanim u tabeli 4:to the above mixture to avoid the formation of lumps. The solution is mixed until homogenous. The remainder of denatured ethyl alcohol and isopropyl alcohol is then added to the coating mixture and mixing is continued until a homogeneous solution is obtained. The coating solution is then passed through a DeBee Homogenizer (nozzle size 7, process pressure 8500 ± 2000 psi and background pressure 1000 ± 250 psi). The homogenized coating solution is then sprayed onto the tablet cores in a tablet coater (O'Hara 36 Side Vent) with the process parameters shown in Table 4:
Presvlačenje jezgara tableta rastvorom za prevlaku za kontrolisano otpuštanje se nastavlja dok se ne ostvari dobitak težine od oko 24 mg (opseg vlažne prevlake od oko 22 do oko 26 mg) i dobitakCoating of the tablet cores with the controlled release coating solution is continued until a weight gain of about 24 mg (wet coating range of about 22 to about 26 mg) is achieved and a gain
težine od oko 29 mg (opseg vlažne prevlake od oko 27 do oko 31 mg), za jezgra tableta od 150 mg i od 300 mg respektivno. Kada se postigne željeni dobitak težine, prevlačenje se zaustavi i presvučenaweight of about 29 mg (wet coating range from about 27 to about 31 mg), for 150 mg and 300 mg tablet cores respectively. When the desired weight gain is achieved, the coating is stopped and coated
jezgra tableta se suše pri temperaturi ulaznog vazduha od oko 35 ± 2°C sa brzinom šolje postavljenom na oko 2 o/min. Osušena i ohlađena jezgra tableta se zatim presvlače formulacijom barijere za vlagu predstavljenom u tabeli 5:the tablet cores are dried at an inlet air temperature of about 35 ± 2°C with the cup speed set at about 2 rpm. The dried and cooled tablet cores are then coated with the moisture barrier formulation presented in Table 5:
Kombinacija plastifikatora, poželjno je pelietilen glikol 1450 i trietil citrat, se najpre rastvaraju u delu prečišćene vode i mešaju do homogenosti. Dok se rastvor plastifikatora mesa, kopolimer metakrilne kiseline, poželjno je Eudragit® L 30 D-55, se propušta kroz sito sa mešom od 0,3 mm u odvojenoj posudi. Zatim se dodaje rastvor plastifikatora kopolimeru metakrilne kiseline i meša dok se ne postigne homogen rastvor. Dok se meša rastvor kopolimera/plastifikatora, pojačavaš permeacije, poželjno silicijum dioksid, se rastvara u ostatku vode i meša u mikseru velike brzine dok se ne postigne homogenost suspenzije. Konačni rastvor barijere za vlagu ostvaruje se mešanjemThe combination of plasticizers, preferably polyethylene glycol 1450 and triethyl citrate, are first dissolved in a portion of purified water and mixed until homogeneous. While the meat plasticizer solution, methacrylic acid copolymer, preferably Eudragit® L 30 D-55, is passed through a 0.3 mm sieve in a separate container. The plasticizer solution is then added to the methacrylic acid copolymer and mixed until a homogeneous solution is achieved. While the copolymer/plasticizer solution is being mixed, the permeation enhancer, preferably silica, is dissolved in the rest of the water and mixed in a high-speed mixer until a homogenous suspension is achieved. The final moisture barrier solution is achieved by mixing
rastvora pojačavača permeacije sa smešom kopolimer metakrilne kiseline/plastifikator. Homogenizovan rastvor barijere za vlagu se zatim raspršuje po jezgrima tableta presvučenih prevlakom za kontrolisano otpuštanje u šolji za presvlačenje sa procesnim parametrima prikazanim u tabeli 6:of the permeation enhancer solution with the methacrylic acid copolymer/plasticizer mixture. The homogenized moisture barrier solution is then sprayed onto the controlled release coating coated tablet cores in a coating cup with the process parameters shown in Table 6:
Barijera za vlagu se nanosi dok se ne postigne dobitak težine od oko 7 mg (opseg vlažne prevlake od oko 6,3 do oko 7,7 mg) i dobitak težine od oko 10,5 mg (opseg vlažne prevlake oko 9,5-11,5 mg), za jezgra tableta sa modifikovanim otpuštanjem sa dozom od 150The moisture barrier is applied until a weight gain of about 7 mg (wet coating range of about 6.3 to about 7.7 mg) and a weight gain of about 10.5 mg (wet coating range of about 9.5-11 .5 mg), for modified-release tablet cores with a dose of 150
mg i od 300 mg respektivno. Kada se postigne željeni dobitak težine, prevlačenje se zaustavi i presvučena jezgra tableta se suše primg and of 300 mg respectively. When the desired weight gain is achieved, the coating is stopped and the coated core tablets are dried at
temperaturi ulaznog vazduha od oko 35 ± 2°C sa brzinom šolje postavljenom na oko 2 o/min.at an inlet air temperature of about 35 ± 2°C with the cup speed set at about 2 rpm.
Presvučene tablete se na kraju štampaju trajnim oznakama korišćenjem crnog mastila, kao što je na primer crno mastilo Opacode® S-l-8090, korišćenjem štampača za tableta (Print International).The coated tablets are finally printed with permanent markings using black ink, such as Opacode® S-1-8090 black ink, using a tablet printer (Print International).
Profil rastvaranja za svaku od tri doze od 150 mg i 300 mg određen je pod sledećim uslovima rastvaranja:The dissolution profile for each of the three doses of 150 mg and 300 mg was determined under the following dissolution conditions:
Medijum: 900 ml_, 0,1N HCIMedium: 900 ml_, 0.1N HCl
Metod: USP aparatura tipa I (150 mg doza)/USP aparatura tipa IIMethod: USP apparatus type I (150 mg dose)/USP apparatus type II
(300mg doza), na 75 o/min i 37°C(300mg dose), na 75 rpm and 37°C
Rezultati su predstavljeni u tabeli 7 kao srednja vrednost u procentima od ukupnog sadržaja bupropion hidrohlorida u presvučenim tabletama:The results are presented in Table 7 as the mean value in percentage of the total content of bupropion hydrochloride in the coated tablets:
Srednji profil rastvaranja za tri različite tablete bupropion hidrohlorida sa modifikovanim otpuštanjem od 150 mg i 300 mg prikazan je na crtežima 1A i 1B, respektivno. Za sve dalje testove i proizvodnju izabrane su formulacije C i C' za doze od 150 mg i 300 mg.The mean dissolution profile for three different bupropion hydrochloride modified-release tablets of 150 mg and 300 mg are shown in Figures 1A and 1B, respectively. For all further tests and production, formulations C and C' were chosen for doses of 150 mg and 300 mg.
2. Stabilnost formulacija tableta sa modifikovanim otpuštanjem2. Stability of tablet formulations with modified release
Ove formulacije ne sadrže stabilizator. Da bi se odredila stabilnost bupropion hidrohlorida u odsustvu stabilizatora, sprovedeni su testovi stabilnosti kako pod uslovima ubrzanih uslova u toku 6 meseci na 40°C ± 2°C/75%Rel.vlaž. ± 5% Rel.vlaž. i pod uslovima dugoročne stabilnosti u toku 12 i 18 meseci na 25°C ± 2°C/60% Rel.vlaž. ± 5% Rel.vlaž. Ne kraju datog vemenskog perioda, tablete su analizirane na nečistoće koje su rezultat razgradnje bupropion hidrohlorida pomoću HPLC. Proizvodi razgradnje su obuhvatali one koji su navedeni u USP (26. izdanje, pp 281) i bilo koje druge maksimume koji su se pojavili na hromatogramu. Rezultati analize stabilnosti i za ubrzane i dugoročne uslove kako za forme sa dozama od 150 mg i 300 mg prikazani su u tabelama 8, 9 i 10:These formulations do not contain a stabilizer. In order to determine the stability of bupropion hydrochloride in the absence of stabilizers, stability tests were conducted both under accelerated conditions for 6 months at 40°C ± 2°C/75%RH. ± 5% Rel. humidity and under conditions of long-term stability during 12 and 18 months at 25°C ± 2°C/60% Rel.humidity. ± 5% Rel. humidity At the end of the given time period, the tablets were analyzed for impurities resulting from the degradation of bupropion hydrochloride by HPLC. Degradation products included those listed in the USP (26th edition, pp 281) and any other peaks that appeared on the chromatogram. The results of the stability analysis for both accelerated and long-term conditions for the 150 mg and 300 mg dosage forms are shown in Tables 8, 9 and 10:
Podaci o stabilnosti za 48 meseci su procenjeni statističkom analizom isticanja za svaku tabletnu dozu. Grafici isticanja su prikazani na slikama 2A i 2B. Specifikacije su izvedene na osnovu raspoloživih podataka, procenjivanjem nivoa gornjeg intervala poverenja projektovanog na 48 meseci.The 48-month stability data were evaluated by statistical significance analysis for each tablet dose. Highlight plots are shown in Figures 2A and 2B. The specifications were derived based on the available data, by estimating the level of the upper confidence interval projected at 48 months.
PRIMER 2FIRST 2
1. Barijera za vlagu nije enterična prevlaka1. The moisture barrier is not an enteric coating
Svrha ove studije je bila da pokaže da tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku nisu presvučene enteričnom prevlakom. Formulacija sa modifikovanim otpuštanjem se bazira na jezgru tablete koje sadrži bupropion hidrohlorid, vezivo i lubrikant. Jezgro tablete je presvučeno prevlakom za kontrolisano otpuštanje, koja ima funkciju da kontroliše otpuštanje bupropion hidrohlorida. Jezgra tableta presvučena prevlakom za kontrolisano otpuštanje se zatim prevlače barijerom za vlagu, koja suštinski zadržava ili usporava apsorpciju vlage.The purpose of this study was to demonstrate that the modified release bupropion hydrochloride tablets of the invention are not enteric coated. The modified-release formulation is based on a tablet core containing bupropion hydrochloride, a binder and a lubricant. The tablet core is coated with a controlled-release coating, which has the function of controlling the release of bupropion hydrochloride. The controlled-release coating-coated tablet cores are then coated with a moisture barrier, which essentially retains or slows the absorption of moisture.
Otpuštanje leka je mereno spektrofotometrijski dvostepenim postupkom rastvaranja uz korišćenje uslova za rastvaranje za enterične prevlake prema USP metod B (šolja na 75 o/min) da bi se procenio integritet tablete. Rezultati ovih ispitivanja su prikazani u tabelama 11 i 12:Drug release was measured spectrophotometrically by a two-step dissolution procedure using dissolution conditions for enteric coatings according to USP Method B (cup at 75 rpm) to assess tablet integrity. The results of these tests are shown in tables 11 and 12:
Pri kiseloj pH (0,1N HCI), oko 7% bupropion hidrohlorida se otpusti u okviru 2 časa, međutim pri pH 6,8 oko 21% bupropion hidrohlorida se otpusti u okviru 1 časa. Shodno tome, tableta sa modifikovanim otpuštanjem prema pronalasku ne zadovoljava USP zahtev za tabletu sa enteričnom prevlakom, tj. posle 2 časa u kiseloj sredini (0,1N HCI) ni jedna pojedinačna vrednost ne prevazilazi vrednost od 10% rastvorenog aktivnog leka i ne manje od 75% je rastvoreno na 45 min u puferu od pH 6,8.At acidic pH (0.1N HCl), about 7% of bupropion hydrochloride is released within 2 hours, however at pH 6.8, about 21% of bupropion hydrochloride is released within 1 hour. Accordingly, the modified-release tablet according to the invention does not meet the USP requirement for an enteric-coated tablet, i.e. after 2 hours in an acidic environment (0.1N HCI), not a single value exceeds the value of 10% of dissolved active drug and no less than 75% was dissolved in 45 min in a buffer of pH 6.8.
Funkcionisanje barijere za vlagu kao neenterične prevlake jeThe function of the moisture barrier as a non-enteric coating is
dalje pokazano direktnim presvlačenjem jezgara tableta od 15 mg barijerom za vlagu. U tabeli 13 prikazano je da rezultati rastvaranja (prva 2 časa u kiseloj sredini) nisu u skladu sa USP zahtevima za tabletu sa enteričnom prevlakom. ,further demonstrated by directly coating the 15 mg tablet cores with a moisture barrier. Table 13 shows that the dissolution results (the first 2 hours in an acidic environment) do not comply with the USP requirements for an enteric-coated tablet. ,
Sredina: 900 ml 0,1 N HCIMedium: 900 mL 0.1 N HCl
Ispitivanje sa puferom nije izvedeno zato što je otpuštanje bilo visoko u kiseloj sredini.The buffer test was not performed because the release was high in the acidic medium.
2. Barijera za vlagu funkcioniše tako da suštinski sprečava ili usporava apsorpciju vlage.2. The moisture barrier functions to substantially prevent or slow the absorption of moisture.
Funkcionalnost barijere za vlagu kao prevlake koja suštinski sprečava ili usporava apsorpciju vlage bila je potvrđena određivanjem sadržaja vlage po Karl-Fišeru bilo jezgara tableta presvučenih prevlakom za kontrolisano otpuštanje ili jezgara tableta presvučenih barijerom za vlagu za jezgra tableta od 300 mg. SpravljanjeThe functionality of the moisture barrier as a coating that substantially prevents or retards moisture absorption was confirmed by determining the Karl-Fisher moisture content of either the controlled release coating coated tablet cores or the moisture barrier coated tablet cores for the 300 mg tablet cores. Making up
formulacija se vrši kao što je opisano u primeru 1. Odgovarajuće presvučene tablete su postavljene odvojeno pod ubrzanim uslovimaformulation is carried out as described in Example 1. Appropriate coated tablets are placed separately under accelerated conditions
(40°C ± 2°C/75%Rei.vlaž. ± 5% Rel.vlaž.) u otvorenoj staklenoj šolji 10 dana. Kao što je prikazano u tabeli 14, sadržaji vlage za jezgra tableta sa prevlakom za kontrolisano otpuštanje viši su nego za jezgra tableta presvučenih barijerom za vlagu.(40°C ± 2°C/75%Rei.humid. ± 5% Rel.humid.) in an open glass cup for 10 days. As shown in Table 14, the moisture contents of the controlled release coated tablet cores are higher than those of the moisture barrier coated tablet cores.
Podaci prikazani u tabelama 13 i 14 prikazuju da barijera za vlagu nema funkciju enterične prevlake kako je to definisano po USP. Umesto toga, podaci pokazuju funkcionisanje barijere za vlagu kao prevlake, koja suštinski sprečava ili usporava apsorpciju vlage.The data shown in Tables 13 and 14 show that the moisture barrier does not function as an enteric coating as defined by the USP. Instead, the data show the moisture barrier functions as a coating, essentially preventing or slowing moisture absorption.
PRIMER 3FIRST 3
Cilj ove studije bio je ispitivanje ekvivalentnosti doza siedećih ispitnih tableta bupropion HCI sa modifikovanim otpuštanjemThe aim of this study was to investigate the equivalence of doses of bupropion HCI modified-release sitting test tablets
od 150 mg i od 300 mg pod uslovima gladovanja. Sprovedena je dvosmerna, otvorena, krosover studija dozne ekvivalentnosti jednokratne doze, pri izgladnjivanju, za dve jačine (150 mg i 300 mg) tableta bupropion HCI sa modifikovanim otpuštanjem prema pronalasku. Tablete sa modifikovanim otpuštanjem prema pronalasku davane su jednom dnevno normalnim zdravim nepušačkim muškim i ženskim subjektima.of 150 mg and of 300 mg under fasting conditions. A two-way, open-label, crossover dose-equivalence study of a single dose, under fasting conditions, of two strengths (150 mg and 300 mg) of the modified-release bupropion HCI tablets of the invention was conducted. The modified-release tablets of the invention were administered once daily to normal healthy non-smoking male and female subjects.
Postavka studije obuhvatila je dvoperiodičnu, dvotretmansku, krosover postavku jednokratne doze pod uslovima gladovanja. Periodi ispitivanja su prekidani tronedeljnim periodima izbacivanja. U ispitivanje je bilo uključeno ukupno 36 subjekata (19 muških, 17 ženskih) od kojih je 35 (19 muških, 16 ženskih) završilo ispitivanje. Subjektima su davani sledeći tretmani:The study setting included a two-period, two-treatment, single-dose crossover setting under fasting conditions. The test periods were interrupted by three-week washout periods. A total of 36 subjects (19 male, 17 female) were included in the study, of which 35 (19 male, 16 female) completed the study. Subjects were given the following treatments:
A) 2x150 mg q.d. tableta bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku oralno uz 250 ml_ vode na sobnoj temperaturi, posle noćnog gladovanja od najmanje 10 časova.A) 2x150 mg q.d. modified-release bupropion hydrochloride tablet according to the invention orally with 250 ml of water at room temperature, after an overnight fast of at least 10 hours.
B) 1x300 mg q.d. tableta bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku oralno uz 250 ml_ vode na sobnoj temperaturi, posle noćnog gladovanja od najmanje 10 časova.B) 1x300 mg q.d. modified-release bupropion hydrochloride tablet according to the invention orally with 250 ml of water at room temperature, after an overnight fast of at least 10 hours.
Grafici profila srednje koncentracije u plazmi (ng/ml_) bupropiona i njegovih metabolita hidroksibupropiona, bupropion treoamino alkokhola i eritroamino alkohola tokom perioda od 120Plots of mean plasma concentration profiles (ng/ml_) of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol and erythroamino alcohol over a period of 120
časova posle davanja formi od 2 x 150 mg jednom dnevno i 1 x 300 mg jednom dnevno prikazani su na crtežima 3A-D respektivno.hours after administration of the 2 x 150 mg once daily and 1 x 300 mg once daily formulations are shown in Figures 3A-D respectively.
Tabele 15a-d prikazuju srednje vrednosti (±SD) farmakokinetičkih podataka za bupropion posle davanja 2 x 150 mg doze jednom dnevno ili 300 mg doze jednom dnevno: rTables 15a-d show the mean (±SD) pharmacokinetic data for bupropion following administration of 2 x 150 mg doses once daily or 300 mg doses once daily: r
Rezultati analize relativne biodostupnosti (2 x 150 mg (q.d.) prema 1 x 300 mg (q.d.) ) za AUC0-inf, AUC0-t, i CmaxResults of relative bioavailability analysis (2 x 150 mg (q.d.) vs. 1 x 300 mg (q.d.) ) for AUC0-inf, AUC0-t, and Cmax
transformisano pomoću prirodnog logaritma pod uslovima gladovanja sumirani su u tabeli 16 za bupropion i njegove metabolite:natural log transformed under fasting conditions are summarized in Table 16 for bupropion and its metabolites:
Podaci pokazuju da su obe tablete u dozi od 150 mg date kao dve tablete jednom dnevno i tableta u dozi od 300 mg data jednom dnevno od tableta sa modifikovanim otpuštanjem prema pronalasku kao što su ovde opisane u primeru 1 ekvivalentne jedne drugima u smislu njihovih farmakokinetičkih parametara za bupropion i njegove metabolite.The data show that both the 150 mg tablet given as two tablets once daily and the 300 mg tablet given once daily of the modified release tablets of the invention as described herein in Example 1 are equivalent to each other in terms of their pharmacokinetic parameters. for bupropion and its metabolites.
PRIMER 4FIRST 4
Sprovedene su četvorosmerna, otvorena, krosover, uporedna studija biodostupnosti pri gladovanju i sa efektom hrane, sa jednokratnom dozom tableta od 150 mg bupropion hidrohlorida ovde opisanih u primeru 1 i Zyban® tableta od 150 mg sa normalnim zdravim nepušačkim muškim i ženskim subjektima, Ova studija je postavljena da bi se ocenila brzina i stepen apsorpcije bupropiona u sitom i gladnom stanju posle uzimanja 150 mg-skih tableta bupropion hidrohlorida sa modifikovanim otpuštanjem kao što su ovde opisane u primeru 1. Paralelno sa tim, u ovoj studiji je ocenjena i brzina i stepen apsorpcije bupropiona u sitom i gladnom stanju posle uzimanja 150 mg-skih tableta Zyban®.A four-way, open-label, crossover, comparative fasting and food-effect bioavailability study of the single-dose bupropion hydrochloride 150 mg tablets described herein in Example 1 and Zyban® 150 mg tablets was conducted in normal healthy non-smoking male and female subjects. was set up to assess the rate and extent of bupropion absorption in the fed and fasted state after ingestion of 150 mg bupropion hydrochloride modified-release tablets as described herein in Example 1. In parallel, this study also assessed the rate and extent absorption of bupropion in a full and fasting state after taking 150 mg Zyban® tablets.
Postavka studije je podrazumevala dvoperiodičnu, dvotretmansku, krosover postavku sa jednokratnom dozom pod uslovima gladovanja i sitosti. Između perioda ispitivanja postojao je dvonedeljni period izbacivanja. U studiju je bilo uključeno 35 subjekata (24 muška, 11 ženskih) od kojih je 32 subjekta (24 muška, 11 ženskih) završilo ispitivanja. Subjektima su davani sledeći tretmani:The study setting was a two-period, two-treatment, single-dose, crossover design under fasted and fed conditions. There was a two-week washout period between test periods. 35 subjects (24 males, 11 females) were included in the study, of which 32 subjects (24 males, 11 females) completed the tests. Subjects were given the following treatments:
A) tablete od 150 mg q.d. bupropion hidrohlorida prema pronalasku pod uslovima gladovanja,A) 150 mg tablets q.d. bupropion hydrochloride according to the invention under fasting conditions,
B) tablete od 150 mg q.d. bupropion hidrohlorida prema pronalasku pod uslovima sitosti,B) 150 mg tablets q.d. bupropion hydrochloride according to the invention under conditions of satiety,
C) tablete Zyban® od 150 mg q.d. pod uslovimaC) Zyban® tablets 150 mg q.d. under conditions
gladovanja, and .starvation, and .
D) tablete Zyban® od 150 mg q.d. pod uslovima sitosti.D) Zyban® tablets 150 mg q.d. under saturation conditions.
Grafici profila srednje koncentracije u plazmi (ng/mL) bupropiona i njegovih metabolita hidroksibupropiona, bupropion treoamino alkokhola i eritroamino alkohola tokom perioda od 72 časa posle davanja tableta od 1 x 150 mg sa modifikovanim otpuštanjem prema pronalasku jednom dnevno i 1 x 150 mg forme jednodnevne doze Zyban® tableta prikazani su na crtežima 4A-E.Mean plasma concentration profiles (ng/mL) of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol, and erythroamino alcohol over a 72-hour period following administration of 1 x 150 mg modified-release tablet of the invention once daily and 1 x 150 mg once-daily formulation doses of Zyban® tablets are shown in Figures 4A-E.
Tabela 17 sadrži srednje vrednosti (±SD) farmakokinetičkih podataka za bupropion posle davanja tableta u dozi od 150 mg prema pronalasku ili na tržištu dostupnih Zyban® tableta prema stanju tehnike pod uslovima gladovanja i sitosti za bupropion i njegove metabolite:Table 17 contains the mean (±SD) pharmacokinetic data for bupropion after administration of 150 mg tablets according to the invention or commercially available Zyban® tablets according to the prior art under fasted and fed conditions for bupropion and its metabolites:
Rezultati analize relativne biodostupnosti (tableta sa modifikovanim otpuštanjem prema pronalasku pri gladovanju u odnosu na sitost) za AUC0-inf, AUC0-t, i Cmax transformisano korišćenjemRelative bioavailability analysis results (modified-release tablet according to the invention under fasted versus full) for AUC0-inf, AUC0-t, and Cmax transformed using
prirodnog logaritma pod uslovima gladovanja i sitost sumarno su dati u tabeli 18 za bupropion i njegove metabolite:of the natural logarithm under conditions of fasting and satiety are summarized in Table 18 for bupropion and its metabolites:
Podaci u tabeli 18 prikazuju da biodostupnost bupropiona i njegovih metabolita ne pokazuje efekat hrane, tj. tablete sa modifikovanim otpuštanjem prema pronalasku koje sadrže bupropion hidrohlorid su bioekvivalentne u prisustvu ili odsustvu hrane kao što jeThe data in Table 18 show that the bioavailability of bupropion and its metabolites does not show the effect of food, ie. The modified-release tablets of the invention containing bupropion hydrochloride are bioequivalent in the presence or absence of food such as
evidentno iz činjenice da 90% Cl odnosa geometrijskih sredina za AUC0-inf (i AUC0-t gde važi) i Cmax u stanju gladovanja prema stanju sitosti nalaze se u okvirima sugerisanih granica po FDA tj. 80-125%.evident from the fact that 90% Cl ratio of geometric means for AUC0-inf (and AUC0-t where applicable) and Cmax in the fasting state to the satiety state are within the limits suggested by the FDA, i.e. 80-125%.
PRIMER 5FIRST 5
Dvostruka, krosover, otvorena, uporedna studija biodostupnosti sa jednokratnom dozom i efektom hrane za tablete bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku od 300 mg kod normalnih zdravih nepušačkih muških i ženskih subjekata.A double-blind, crossover, open-label, single-dose, comparative bioavailability and food effect study of bupropion hydrochloride modified-release tablets according to the invention 300 mg in normal healthy nonsmoking male and female subjects.
Ova studija je postavljena tako da oceni efekat hrane na brzinu i stepen apsorpcije jednodnevne doze tablete od 300 mg bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku pod uslovima jednokratne doze. Postavka studije je uključivala dvoperiodičnu, dvotretmansku krosover postavku sa jednokratnom dozom pod uslovima gladovanja i sitosti. Periodi ispitivanja su prekidani dvonedeljnim periodom izbacivanja. U ispitivanjima je učestvovalo ukupno 36 subjekata (26 muških, 10 ženskih) od kojih je 32 subjekta (23 muška, 9 ženksih) završilo ispitivanja. Subjektima je davano sledeće:This study was designed to evaluate the effect of food on the rate and extent of absorption of a one-day dose of a 300 mg bupropion hydrochloride modified-release tablet according to the invention under single-dose conditions. The study setting included a two-period, two-treatment crossover design with a single dose under fasted and fed conditions. The test periods were interrupted by a two-week washout period. A total of 36 subjects (26 male, 10 female) participated in the tests, of which 32 subjects (23 male, 9 female) completed the test. Subjects were given the following:
A) 1 x 300 mg tableta sa modifikovanim otpuštanjem posle gladovanja od 10 časova.A) 1 x 300 mg tablet with modified release after fasting for 10 hours.
B) 1 x 300 mg tableta sa modifikovanim otpuštanjemB) 1 x 300 mg modified-release tablet
posle doručka sa visokim sadržajem masti.after a high-fat breakfast.
Grafici profila srednje koncentracije u plazmi (ng/mL) bupropiona i njegovih metabolita hidroksibupropiona, bupropion treoamino alkokhola i eritroamino alkohola tokom perioda od 120 časova posle davanja formi od 1 x 300 mg tablete sa modifikovanim otpuštanjem prema pronalasku jednom dnevno pod uslovima sitosti i gladovanja prikazani su na crtežima 5A-D respektivno.Graphs of the mean plasma concentration profile (ng/mL) of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol and erythroamino alcohol over a period of 120 hours after administration of the 1 x 300 mg modified-release tablet form of the invention once daily under fed and fasted conditions are shown are in Figures 5A-D respectively.
Tabela 19 daje srednje vrednosti (±SD) farmakokinetičkih podataka za bupropion i njegove metabolite posle davanja 300 mg-skih tableta sa modifikovanim otpuštanjem prema pronalasku pod uslovima gladovanja i sitosti:Table 19 provides the mean (±SD) pharmacokinetic data for bupropion and its metabolites following administration of 300 mg modified-release tablets of the invention under fasted and fed conditions:
Rezultati analize relativne biodostupnosti (sito prema gladnom stanju) za AUC0-jnf, AUC0-t i Cmax transformisano korišćenjemRelative bioavailability analysis results (fed vs. fasted) for AUC0-jnf, AUC0-t and Cmax transformed using
prirodnog logaritma i pod uslovima gladovanja i sitosti za bupropion i njegove metabolite sumarno su prikazani u tabeli 20:of the natural log and under fasting and satiety conditions for bupropion and its metabolites are summarized in Table 20:
Podaci u tabeli 20 pokazuju da biodostupnost bupropiona i njegovih metabolita iz tableta bupropion hidrohlorida sa modifikovanim otpuštanjem u dozi od 300 mg prema pronalasku ne pokazuje efekat hrane kao što je evidentno iz činjenice da je 90% Cl odnosa geometrijskih sredina za AUC0-inf (i AUC0-t gde važi) i Cmax u stanjuThe data in Table 20 show that the bioavailability of bupropion and its metabolites from the modified-release bupropion hydrochloride 300 mg tablets of the invention does not show an effect of food as evident from the fact that the 90% Cl ratio of the geometric means for AUC0-inf (and AUC0 -t where applicable) and Cmax in the condition
sitosti u odnosu na stanje gladovanja nalaze se u okvirima sugerisanih granica po FDA tj. 80-125%.satiety compared to the state of starvation is within the suggested limits according to the FDA, i.e. 80-125%.
PRIMER 6FIRST 6
Sprovedena je dvosmerna, krosover, otvorena, uporedna studija biodostupnosti sa ustaljenim stanjem, gladovanjem i višekratnom dozom za jednodnevnu tabletu bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku od 300 mg u odnosu na tri puta dnevnu tabletu VVellbutrin® od 100 mg sa trenutnim otpuštanjem prema stanju tehnike kod normalnih zdravih nepušačkih muških i ženskih subjekata.A two-way, crossover, open-label, comparative, steady-state, fasting, and multiple-dose bioavailability study was conducted for a once-daily modified-release bupropion hydrochloride 300 mg tablet of the invention versus a three-times-daily VVellbutrin® 100 mg immediate-release tablet according to the prior art. in normal healthy non-smoking male and female subjects.
Studija je bila postavljena kao dvoperiodna dvotretmanska krosover studija sa većom i višekratnom dozom pod uslovima gladovanja uz dvonedeljni period izbacivanja između dva perioda ispitivanja. U studiju je bilo uključeno ukupno 40 subjekata (27 muškaraca, 13 žena) od kojih je 30 subjekata (22 muškaraca, 8 žena) završilo ispitivanja. Subjekti su bili podvrgnuti sledećim doznim režimima:The study was designed as a two-period, two-treatment, multiple-dose crossover study under fasted conditions with a two-week washout period between the two study periods. A total of 40 subjects (27 men, 13 women) were included in the study, of which 30 subjects (22 men, 8 women) completed the tests. Subjects were subjected to the following dosing regimens:
A) Wellbutrin® 100 mg tablete su davane oralno na 0.0 časova (počinjući od 7.00 ujutro) na dane 1, 2 i 3 (b.i.d.) sa 240 mL vode na sobnoj temperaturi posle noćnog gladovanja od najmanje 10 časova. Svi subjekti su takođe primili i drugu dozu od jedne VVellbutrin® 100 mg tablete na 12.0 časova sa 240 ml_ vode na sobnoj temperaturi posle gladovanja od najmanje 1 časa. Na dane 4-13 subjekti su primili po jednu tabletu bupropion hidrohlorida od 300 mg prema pronalasku na 0.0 časova (počinjući od 7.00 ujutro) sa 240 mL vode na sobnoj temperaturi posle noćnog gladovanja od najmanje 10 časova.A) Wellbutrin® 100 mg tablets were administered orally at 0.0 hours (starting at 7.00 am) on days 1, 2 and 3 (b.i.d.) with 240 mL of water at room temperature after an overnight fast of at least 10 hours. All subjects also received a second dose of one Wellbutrin® 100 mg tablet at 12.0 hours with 240 ml of water at room temperature after fasting for at least 1 hour. On days 4-13, subjects received one bupropion hydrochloride 300 mg tablet according to the invention at 0.0 hours (starting at 7.00 am) with 240 mL of water at room temperature after an overnight fast of at least 10 hours.
B) VVellbutrin® 100 mg tablete su davane oralno na 0.0 časova (počinjući od 7.00 ujutro) na dane 1, 2 i 3 (b.i.d.) sa 240 mL vode na sobnoj temperaturi posle noćnog gladovanja od najmanje 10 časova. Svi subjekti su takođe primili i drugu dozu od jedne VVellbutrin® 100 mg tablete na 12.0 časova sa 240 mL vode na sobnoj temperaturi posle gladovanja od najmanje 1 časa. Na dane 4-13 subjekti su primili po jednu tabletu VVellbutrin® od 100 mg na 0.0 časova (počinjući od 7.00 ujutro) sa 240 mL vode na sobnoj temperaturi posle noćnog gladovanja od najmanje 10 časova. Svi subjekti su zatim primili drugu dozu od jedne VVellbutrin® 100 mg tablete na 6.0 časova sa 240 mL vode na sobnoj temperaturi posle gladovanja od najmanje 1 čas. Svi subjekti su zatim primili drugu dozu od jedne VVellbutrin® 100 mg tablete na 12.0 časova sa 240 mL vode na sobnoj temperaturi posle gladovanja od najmanje 1 čas.B) VWellbutrin® 100 mg tablets were administered orally at 0.0 hours (starting at 7.00 am) on days 1, 2 and 3 (b.i.d.) with 240 mL of water at room temperature after an overnight fast of at least 10 hours. All subjects also received a second dose of one Wellbutrin® 100 mg tablet at 12.0 hours with 240 mL of water at room temperature after fasting for at least 1 hour. On days 4-13, subjects received one VWellbutrin® 100 mg tablet at 0.0 hours (starting at 7.00 am) with 240 mL of water at room temperature after an overnight fast of at least 10 hours. All subjects then received a second dose of one Wellbutrin® 100 mg tablet every 6.0 hours with 240 mL of water at room temperature after fasting for at least 1 hour. All subjects then received a second dose of one VWellbutrin® 100 mg tablet at 12.0 hours with 240 mL of water at room temperature after fasting for at least 1 hour.
Grafici profila srednje koncentracije u plazmi (ng/mL) bupropiona i njegovih metabolita hidroksibupropiona, bupropion treoamino alkokhola i eritroamino alkohola tokom perioda ispitivanja posle davanja formi od 1 x 300 mg tablete sa modifikovanim otpuštanjem prema pronalasku jednom dnevno i tableta VVellbutrin® 3Plots of mean plasma concentration profiles (ng/mL) of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol and erythroamino alcohol during the study period after administration of 1 x 300 mg modified-release tablet form of the invention once daily and VWellbutrin® 3 tablets
x 100 mg prikazani su na crtežima 6A-E respektivno.x 100 mg are shown in Figures 6A-E respectively.
Tabela 21 daje srednu vrednost (±SD) farmakokinetičkih podataka za bupropion posle davanja jednom dnevno po tabletu sa modifikovanim otpuštanjem od 300 mg prema pronalasku ili tri puta dnevno na tržištu dostupne tablete VVellbutrin® 100 mg prema stanju tehnike:Table 21 provides the mean (±SD) pharmacokinetic data for bupropion following once-daily administration of a 300 mg modified-release tablet according to the invention or three times daily of a commercially available VVellbutrin® 100 mg tablet according to the prior art:
Rezultati analize relativne biodostupnosti (tableta sa modifikovanim otpuštanjem prema pronalasku u odnosu na VVellbutrin®) za AUC0-xi Cmax za bupropion i njegove metaboliteResults of relative bioavailability analysis (modified release tablet according to the invention compared to VWellbutrin®) for AUC0-xi Cmax for bupropion and its metabolites
transformisano korišćenjem prirodnog logaritma dati su sumarno u tabeli 22:transformed using the natural logarithm are summarized in table 22:
Podaci u tabelama 21 i 22 pokazuju da je tableta od 300 mg sa modifikovanim otpuštanjem prema pronalasku uzimana jednomThe data in Tables 21 and 22 show that the 300 mg modified release tablet of the invention was taken once
dnevno bioekvivalentna sa tabletom Wellbutrin® u dozi od 100 mg sa trenutnim otpuštanjem uzimanom tri puta dnevno.daily bioequivalent to Wellbutrin® 100 mg immediate-release tablet taken three times daily.
PRIMER 7FIRST 7
Sprovedena je dvosmerna, krosover, otvorena, višedozna uporedna studija biodostupnosti sa ustaljenim stanjem i uslovima gladovanja za tablete sa modifikovanim otpuštanjem bupropion hidrohlorida prema pronalasku u odnosu na proizvod od 150 mg firme Zyban® dostupan na tržištu iz stanja tehnike kod normalnih zdravih nepušačkih muških i ženskih subjekata. Studija je postavljena tako da uporedi biodostupnost forme sa dozom od 300 mg q.d. tableta bupropion hidrohlorida prema pronalasku u odnosu na tablete Zyban® od 150 mg b.i.d. dostupne na tržištu iz stanja tehnike.A two-way, crossover, open-label, multiple-dose comparative bioavailability study under steady-state and fasting conditions was conducted for the bupropion hydrochloride modified-release tablets of the invention versus the commercially available Zyban® 150 mg product from the prior art in normal healthy non-smoking male and female subjects. subjects. The study was designed to compare the bioavailability of the formulation with a dose of 300 mg q.d. bupropion hydrochloride tablet according to the invention compared to Zyban® tablets 150 mg b.i.d. available on the market from the state of the art.
Studija je postavljena dvoperiodno, dvotretmanski, sa višekratnim doziranjem i krosoverom, pod uslovima gladovanja.The study was set up in two periods, two treatments, with multiple dosing and crossover, under fasting conditions.
Periodi ispitivanja su prekidani dvonedeljnim intervalima izbacivanja. U studiju je bilo uključeno ukupno 54 subjekata (40 muškaraca, 14 žena) od kojih je 49 subjekata (37 muškaraca, 12 žena) završilo ispitivanja. Subjektima su davane tablete od 150 mg q.d. Zyban® od dana 1-3 ispitivanja. Posle dana 4-17 davani su:The test periods were interrupted by two-week washout intervals. A total of 54 subjects (40 men, 14 women) were included in the study, of which 49 subjects (37 men, 12 women) completed the tests. Subjects were given tablets of 150 mg q.d. Zyban® from days 1-3 of the trial. After days 4-17 were given:
A) Tablete od 300 mg q.d. bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku.A) Tablets of 300 mg q.d. modified release bupropion hydrochloride according to the invention.
B) 150 mg b.i.d. Zyban® tableta.B) 150 mg b.i.d. Zyban® tableta.
Grafici profila srednje koncentracije u plazmi (ng/mL) bupropiona i njegovih metabolita hidroksibupropiona, bupropion treoamino alkokhola i eritroamino alkohola tokom perioda ispitivanja posle davanja formi od 1 x 300 mg tablete sa modifikovanim otpuštanjem prema pronalasku jednom dnevno i 2 x 150 mg (b.i.d.) Zyban® tableta pod uslovima gladovanja prikazani su na crtežima 7A-E respektivnoMean plasma concentration profiles (ng/mL) of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol and erythroamino alcohol during the study period after administration of 1 x 300 mg modified-release tablet form of the invention once daily and 2 x 150 mg (b.i.d.) Zyban® tablets under fasting conditions are shown in Figures 7A-E respectively
Tabela 23 daje srednje vrednosti (±SD) farmakokinetičkih podataka za bupropion posle davanja jednom dnevno tablete sa modifikovanim otpuštanjem od 300 mg prema pronalasku ili 150 mg b.i.d. Zyban® tablete iz stanja tehnike dostupne na tržištu:Table 23 provides the mean (±SD) pharmacokinetic data for bupropion following once daily administration of a 300 mg modified release tablet according to the invention or 150 mg b.i.d. State-of-the-art Zyban® tablets available on the market:
Rezultati analize relativne biodostupnosti (tableta sa modifikovanim otpuštanjem prema pronalasku u odnosu na Zyban®) za AUC0-t, Cmax i Cmin za bupropion i njegove metaboliteResults of relative bioavailability analysis (modified-release tablets of the invention vs. Zyban®) for AUC0-t, Cmax, and Cmin for bupropion and its metabolites
transformisano korišćenjem prirodnog logaritma dati su sumarno u tabeli 24:transformed using the natural logarithm are summarized in table 24:
Podaci u tabelama 23 i 24 pokazuju da je tableta od 300 mg (q.d.) bupropion hidrohlorida sa modifikovanim otpuštanjem prema pronalasku bioekvivalentna tableti Zyban® od 150 mg b.i.d sa retard režimom otpuštanja koja je dostupna na tržištu iz stanja tehnike.The data in Tables 23 and 24 show that the modified-release bupropion hydrochloride 300 mg (q.d.) tablet of the invention is bioequivalent to the commercially available Zyban® 150 mg b.i.d. delayed-release tablet.
PRIMER 8 (UPOREDNI PRIMER)EXAMPLE 8 (COMPARATIVE EXAMPLE)
Spravljene su formulacije od 150 mg i 300 mg bupropion hidrohlorida prema patentu US Patent br. 6,143,327 i procenjeniFormulations of 150 mg and 300 mg of bupropion hydrochloride were made according to US Patent no. 6,143,327 and estimated
farmakokinetički parametri i iz podataka o relativnoj biodostupnosti procenjena bioekvivalentnost. Korišćene formulacije o proporcijama komponenti u jezgru, prvoj i drugoj prevlaci prikazane su u tabeli 25pharmacokinetic parameters and bioequivalence estimated from data on relative bioavailability. The formulations used on the proportions of the components in the core, first and second coating are shown in Table 25
Tablete su izrađene prema patentu '327.The tablets are made according to the '327 patent.
Sprovedena je trosmerna, višekratno dozna, otvorena, uporedna pilot studija biodostupnosti tableta bupropion hidrohlorida (2 x 150 mg q.d.) spravljenih prema patentu '327 ("formulacija patenta 327") u odnosu na Zyban® tablete sa retard režimom otpuštanja (1 x 150 mg b.i.d.) i Wellbutrin® tablete (t.i.d.) dostupne na tržištu, kod normalniih zdravih pušačkih i nepušačkih muških dobrovoljaca. Svrha studije bila je da se oceni relativna biodostupnost bupropion hidrohlorida od 150 mg formulacije patenta 327 (2 x 150 mg q.d.) u odnosu na Zyban® 150 mg tablete sa retard otpuštanjem (1 x 150 mg b.i.d) i Wellbutrin® 100 mg tablete (1 x 100 mg t.i.d.) pod uslovima jednokratne doze ili gladovanja sa ustaljenim stanjem.A three-way, multiple-dose, open-label, comparative pilot study of the bioavailability of bupropion hydrochloride tablets (2 x 150 mg q.d.) formulated according to the '327 patent ("327 patent formulation") versus Zyban® sustained-release tablets (1 x 150 mg b.i.d.) and commercially available Wellbutrin® tablets (t.i.d.) in normal healthy smoking and non-smoking male volunteers. The purpose of the study was to evaluate the relative bioavailability of bupropion hydrochloride 150 mg of the patent 327 formulation (2 x 150 mg q.d.) compared to Zyban® 150 mg delayed-release tablets (1 x 150 mg b.i.d.) and Wellbutrin® 100 mg tablets (1 x 100 mg t.i.d.) under single-dose or steady-state fasting conditions.
Tablela 26 prikazuje profile srednjih vrednosti koncentracija (± SD) bupropiona (ng/mL) u vremenu pod uslovima jednokratne doze:Table 26 shows profiles of mean (± SD) bupropion (ng/mL) concentrations over time under single-dose conditions:
U tabeli 27 date su srednje vrednosti (± SD) farmakokinetičkih parametara za bupropion posle davanja tableta prikazanih u tabeli 25:Table 27 gives the mean (± SD) pharmacokinetic parameters for bupropion after administration of the tablets shown in Table 25:
Rezultati analize relativne biodostupnosti za AUC0-24 (ng.h/mL) i Cmax (ng/mL) priazani u tabeli 27, transformisani korišćenjem prirodnog algoritma prikazani su u tabeli 28:The results of the relative bioavailability analysis for AUC0-24 (ng.h/mL) and Cmax (ng/mL) presented in Table 27, transformed using the natural algorithm are shown in Table 28:
U tabeli 29 prikazani su profili srednjih vrednosti koncentracija (± SD) bupropiona (ng/mL) u vremenu za tabletne sastave prikazane u tabeli 25:Table 29 shows the profiles of mean (± SD) bupropion concentrations (ng/mL) over time for the tablet compositions shown in Table 25:
U tabeli 30 prikazane su srednje vrednosti (± SD) farmakokinetičkih podataka za bupropion pod uslovima ustaljenog stanja posle davanja tableta prikazanih u tabeli 25:Table 30 shows the mean (± SD) pharmacokinetic data for bupropion under steady-state conditions after administration of the tablets shown in Table 25:
Rezultati analize relativne biodostupnosti za AUC0-24 (ng.h/mL) i Cmax (ng/mL) priikazani u tabeli 30, transformisani korišćenjem prirodnog algoritma sumarno su prikazani u tabeli 31:The results of the relative bioavailability analysis for AUC0-24 (ng.h/mL) and Cmax (ng/mL) shown in Table 30, transformed using the natural algorithm are summarized in Table 31:
Farmakokinetički podaci i podaci o relativnoj biodostupnosti pokazuju da 90% Cl za formulaciju prema patentu '327 ne pada u okvire sugerisanog FDA opsega od 80%-125% da bi proizvod bio bioekvivalentan. Shodno tome, podaci pokazuju da formulacija patenta '327 nije bioekvivalentna na tržištu dostupnim Zyban®/Wellbutrin® SR (retard) ili Wellbutrin® tabletama.Pharmacokinetic and relative bioavailability data indicate that the 90% Cl for the '327 patent formulation does not fall within the FDA suggested range of 80%-125% for the product to be bioequivalent. Accordingly, the data indicate that the '327 patent formulation is not bioequivalent to commercially available Zyban®/Wellbutrin® SR (retard) or Wellbutrin® tablets.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2003/024700WO2005016318A1 (en) | 2003-08-08 | 2003-08-08 | Modified-release tablet of bupropion hydrochloride |
| Publication Number | Publication Date |
|---|---|
| ME00391Btrue ME00391B (en) | 2011-10-10 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2008-36AME00391B (en) | 2003-08-08 | 2003-08-08 | Modified-release tablet of bupropion hydrochloride |
| MEP-36/08AMEP3608A (en) | 2003-08-08 | 2003-08-08 | Modified-release tablet of bupropion hydrochloride |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-36/08AMEP3608A (en) | 2003-08-08 | 2003-08-08 | Modified-release tablet of bupropion hydrochloride |
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| HR (1) | HRP20050625B1 (en) |
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| SI (1) | SI1575565T1 (en) |
| TN (1) | TNSN06016A1 (en) |
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